掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.csbj.2023.03.006

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：{MDPI} {AG}  

<jats:p>“Liquid biopsy” is an efficient diagnostic tool used to analyse biomaterials in human body fluids, such as blood, saliva, breast milk, and urine. Various biomaterials derived from a tumour and its microenvironment are released into such body fluids and contain important information for cancer diagnosis. Biomaterial detection can provide “real-time” information about individual tumours, is non-invasive, and is more repeatable than conventional histological analysis. Therefore, over the past two decades, liquid biopsy has been considered an attractive diagnostic tool for malignant tumours. Although biomarkers for oral cancer have not yet been adopted in clinical practice, many molecular candidates have been investigated for liquid biopsies in oral cancer diagnosis, such as the proteome, metabolome, microRNAome, extracellular vesicles, cell-free DNAs, and circulating tumour cells. This review will present recent advances and challenges in liquid biopsy for oral cancer diagnosis.</jats:p>

DOI： 10.3390/jpm13020303

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掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

Ribosomes are responsible for the protein synthesis that maintains cellular homeostasis and is required for the rapid cellular division of cancer cells. However, the role of ribosome biogenesis mediators in the malignant behavior of tongue squamous cell carcinoma (TSCC) is unknown. In this study, we found that the expression of RIOK2, a key enzyme involved in the maturation steps of the pre-40S ribosomal complex, was significantly associated with poorer overall survival in patients with TSCC. Further, multivariate analysis revealed that RIOK2 is an independent prognostic factor (hazard ratio, 3.53; 95% confidence interval, 1.19–10.91). Inhibition of RIOK2 expression by siRNA decreased cell growth and S6 ribosomal protein expression in oral squamous cell carcinoma cell lines. RIOK2 knockdown also led to a significant decrease in the protein synthesis in cancer cells. RIOK2 has potential application as a novel therapeutic target for TSCC treatment.

DOI： 10.3390/curroncol30010031

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Surgical treatment is the best curative treatment option for patients with non-small cell lung cancer (NSCLC), but some patients have recurrence beyond the surgical margin even after receiving curative surgery. Therefore, therapies with anti-cancer agents also play an important role perioperatively. In this paper, we review the current status of adjuvant chemotherapy in NSCLC and describe promising perioperative therapies, including molecularly targeted therapies and immune checkpoint inhibitors. Previously reported biomarkers of adjuvant chemotherapy for NSCLC are discussed along with their limitations. Adjuvant chemotherapy after resective surgery was most effective in patients with metastatic lesions located just outside the surgical margin; in addition, these metastatic lesions were the most sensitive to adjuvant chemotherapy. Thus, the first step in predicting patients who have sensitivity to adjuvant therapies is to perform a qualified evaluation of metastatic ability using markers such as actinin-4 (ACTN4). In this review, we discuss the potential use of biomarkers in patient stratification for effective adjuvant chemotherapy and, in particular, the use of ACTN4 as a possible biomarker for NSCLC.

DOI： 10.3390/cancers14184363

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Phosphoproteomic analysis expands our understanding of cancer biology. However, the feasibility of phosphoproteomic analysis using endoscopically collected tumor samples, especially with regards to dynamic changes upon drug treatment, remains unknown in stage IV gastric cancer. Here, we conducted a phosphoproteomic analysis using paired endoscopic biopsy specimens of pre- and post-treatment tumors (Ts) and non-tumor adjacent tissues (NATs) obtained from 4 HER2-positive gastric cancer patients who received trastuzumab-based treatment and from pre-treatment Ts and NATs of 4 HER2-negative gastric cancer patients. Our analysis identified 14,622 class 1 phosphosites with 12,749 quantified phosphosites and revealed molecular changes by HER2 positivity and treatment. An inhibitory signature of the ErbB signaling was observed in the post-treatment HER2-positive T group compared with the pre-treatment HER2-positive T group. Phosphoproteomic profiles obtained by a case-by-case review using paired pre- and post-treatment HER2-positive T could be utilized to discover predictive or resistant biomarkers. Furthermore, these data nominated therapeutic kinase targets which were exclusively activated in the patient unresponded to the treatment. The present study suggests that a phosphoproteomic analysis of endoscopic biopsy specimens provides information on dynamic molecular changes which can individually characterize biologic features upon drug treatment and identify therapeutic targets in stage IV gastric cancer.

DOI： 10.1038/s41598-022-08430-7

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記述言語：英語  

DOI： 10.3233/CBM-229003

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Adjuvant chemotherapy is administered to cancer patients after curative resection but is unnecessary when patients without micro-metastatic lesions undergo a perfectly curative surgical procedure. Patients who need adjuvant chemotherapy are those with micro-metastases outside the resection area that are not detectable by imaging, despite curative resection at primary sites. If biomarkers that reflect metastatic potential could be developed, personalized adjuvant chemotherapy could be provided in clinical settings. Actinin-4 (ACTN4, gene name ACTN4) is an actin-bundling protein identified in 1998 as a novel molecule involved in cancer invasion and metastasis. Overexpression of actinin-4 protein in cancer cells leads to an invasive phenotype, and patients with gene amplification of ACTN4 have a worse prognosis than patients with a normal copy number for cancers of the pancreas, lung, and salivary glands, among others. This review summarizes the biological roles of actinin-4 in cancer invasion and metastasis and examines the potential usefulness of actinin-4 as a biomarker for evaluation of metastatic ability.

DOI： 10.1272/jnms.JNMS.2022_89-118

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Intraductal papillary mucinous neoplasms (IPMNs) are premalignant lesions of pancreatic cancer. An accurate serum biomarker, which allows earlier identification of asymptomatic individuals with high-risk for developing cancer, is of urgent need. Apolipoprotein A2-isoforms (apoA2-i) have previously been identified as biomarkers in pancreatic cancer. This study investigates a potential clinical application of the serum apoA2-i for risk stratification of IPMN and associated cancer. The concentrations of apoA2-i were retrospectively determined in 523 patient sera specimen, composed of 305 IPMNs with preinvasive lesions with different grades of dysplasia and invasive cancer, 140 pancreatic ductal adenocarcinoma, 78 with other cystic lesions and healthy controls cohorts, using an apoA2-i enzyme-linked immunosorbent assay kit. The diagnostic performance of serum apoA2-i was assessed and compared to routine clinical marker CA 19-9. ApoA2-i levels were significantly reduced in all IPMN samples regardless of stage compared to healthy controls. Receiver operating characteristic curve analysis of IPMNs with high-grade dysplasia and IPMN with associated carcinoma revealed the area under curve (AUC) of 0.91 and >0.94, respectively. The respective sensitivities were 70% and 83% with a specificity of 95%, and significantly higher than the gold standard biomarker CA 19-9. AUC values of apoA2-i for detecting IPMN-associated carcinoma of colloid and ductal subtypes were 0.990 and 0.885, respectively. ApoA2-i has the potential to early detect the risk of malignancy of patients with IPMN. The serological apoA2-i test in combination with imaging modalities could help improve the diagnosis of IPMN malignancy. Further validation in larger and independent international cohort studies is needed.

DOI： 10.1002/ijc.33875

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although adjuvant tegafur/uracil (UFT) is recommended for patients with completely resected stage I non-small-cell lung cancer (NSCLC) in Japan, only one-third of cases has received adjuvant chemotherapy (ADJ) according to real-world data. Therefore, robust predictive biomarkers for selecting ADJ or observation (OBS) without ADJ are needed. Patients who underwent complete resection of stage I lung adenocarcinoma with or without adjuvant UFT were enrolled. The status of ACTN4 gene amplification was analyzed by FISH. Statistical analyses to determine whether the status of ACTN4 gene amplification affected recurrence-free survival (RFS) were carried out. Formalin-fixed, paraffin-embedded samples from 1136 lung adenocarcinomas were submitted for analysis of ACTN4 gene amplification. Ninety-nine (8.9%) of 1114 cases were positive for ACTN4 gene amplification. In the subgroup analysis of patients aged 65 years or older, the ADJ group had better RFS than the OBS group in the ACTN4-positive cohort (hazard ratio [HR], 0.084, 95% confidence interval [CI], 0.009-0.806; P = .032). The difference in RFS between the ADJ group and the OBS group was not significant in ACTN4-negative cases (all ages: HR, 1.214; 95% CI, 0.848-1.738; P = .289). Analyses of ACTN4 gene amplification contributed to the decision regarding postoperative ADJ for stage I lung adenocarcinomas, preventing recurrence, improving the quality of medical care, preventing the unnecessary side-effects of ADJ, and saving medical costs.

DOI： 10.1111/cas.15228

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Though pancreatic cancer is uncommon, with an age-adjusted annual incidence of 12.9 cases per 100,000 person-years, it is considered a refractory cancer due to the mortality of 11.0 per 100,000 person-years. To efficiently identify patients with potentially surgically-curable pancreatic cancer, high-risk individuals (HRIs) for pancreatic cancer should be identified by easily and minimally invasive methods from the general population. We have identified unique processing patterns in the C-terminal amino acids of apolipoprotein A2 homodimer in the blood of patients with pancreatic cancer and in HRIs, and we called them apoA2-isoforms (apoA2-i). We then established an enzyme-linked immunosorbent assay (ELISA) to measure circulating apoA2-i in the blood stream. The diagnostic accuracy of apoA2-i to distinguish pancreatic cancer HRIs was verified by several retrospective studies, blind testing with the National Cancer Institute (NCI) Early Detection Research Network (EDRN), a prospective study with prediagnostic samples organized by the European Prospective Investigation into Cancer and Nutrition (EPIC) study, and the prospective screening study of pancreatic cancer in Kobe.The apoA2-i blood test is a potential biomarker to identify HRIs and the curative stage of pancreatic cancer in the general population.

DOI： 10.3233/CBM-210198

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：英語   出版者・発行元：(一社)日本癌治療学会  

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掲載種別：研究論文（学術雑誌）  

The authors regret that there are 3 grammatical typos in the abstract published. Below please find the corrected abstract: Chemosensitivity to cisplatin derivatives varies among individual patients with intractable malignancies including ovarian cancer, while how to unlock the resistance remain unknown. Ovarian cancer tissues were collected after the debulking surgery in discovery- (n = 135) and validation- (n = 47) cohorts, to be analyzed with high-throughput automated immunohistochemistry which identified cystathionine γ-lyase (CSE) as an independent marker distinguishing non-responders from responders to post-operative platinum-based chemotherapy. We aimed to identify CSE-derived metabolites responsible for chemoresistant mechanisms: gold-nanoparticle (AuN)-based surface-enhanced Raman spectroscopy (SERS) was used to enhance electromagnetic fields which enabled to visualize multiple sulfur-containing metabolites through detecting scattering light from Au–S vibration two-dimensionally. Clear cell carcinoma (CCC) which turned out less sensitive to cisplatin than serous adenocarcinoma was classified into two groups by the intensities of SERS intensities at 480 cm-1; patients with greater intensities displayed the shorter overall survival after the debulking surgery. The SERS signals were eliminated by topically applied monobromobimane that breaks sulfane-sulfur bonds of polysulfides to result in formation of sulfide dibimane which was detected at 580 cm-1, manifesting the presence of polysulfides in cancer tissues. CCC-derived cancer cell lines in culture were resistant against cisplatin, but treatment with ambroxol, an expectorant degrading polysulfides, renders the cells CDDP-susceptible. Co-administration of ambroxol with cisplatin significantly suppressed growth of cancer xenografts in nude mice. Furthermore, polysulfides, but neither glutathione nor hypotaurine, attenuated cisplatin-induced disturbance of DNA supercoiling. Polysulfide detection by on-tissue SERS thus enables to predict prognosis of cisplatin-based chemotherapy. The current findings suggest polysulfide degradation as a stratagem unlocking cisplatin chemoresistance. The authors would like to apologise for any inconvenience caused.

DOI： 10.1016/j.redox.2021.102028

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The epidermal growth factor receptor is the only available tyrosine kinase molecular target for treating oral cancer. To improve the prognosis of tongue squamous cell carcinoma (TSCC) patients, a novel molecular target for tyrosine kinases is thus needed. We examined the expression of interleukin-2-inducible T-cell kinase (ITK) using immunohistochemistry, and the biological function of ITK was investigated using biochemical, phosphoproteomic, and metabolomic analyses. We found that ITK is overexpressed in TSCC patients with poor outcomes. The proliferation of oral cancer cell lines expressing ITK via transfection exhibited significant increases in three-dimensional culture assays and murine inoculation models with athymic male nude mice as compared with mock control cells. Suppressing the kinase activity using chemical inhibitors significantly reduced the increase in cell growth induced by ITK expression. Phosphoproteomic analyses revealed that ITK expression triggered phosphorylation of a novel tyrosine residue in trifunctional purine biosynthetic protein adenosine-3, an enzyme in the purine biosynthesis pathway. A significant increase in de novo biosynthesis of purines was observed in cells expressing ITK, which was abolished by the ITK inhibitor. ITK thus represents a potentially useful target for treating TSCC through modulation of purine biosynthesis.

DOI： 10.3390/cancers13133333

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.annonc.2021.05.413

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記述言語：日本語   出版者・発行元：日本分子イメージング学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chemosensitivity to cisplatin derivatives varies among individual patients with intractable malignancies including ovarian cancer, while how to unlock the resistance remain unknown. Ovarian cancer tissues were collected the debulking surgery in discovery- (n = 135) and validation- (n = 47) cohorts, to be analyzed with high-throughput automated immunohistochemistry which identified cystathionine γ-lyase (CSE) as an independent marker distinguishing non-responders from responders to post-operative platinum-based chemotherapy. We aimed to identify CSE-derived metabolites responsible for chemoresistant mechanisms: gold-nanoparticle (AuN)-based surface-enhanced Raman spectroscopy (SERS) was used to enhance electromagnetic fields which enabled to visualize multiple sulfur-containing metabolites through detecting scattering light from Au-S vibration two-dimensionally. Clear cell carcinoma (CCC) who turned out less sensitive to cisplatin than serous adenocarcinoma was classified into two groups by the intensities of SERS intensities at 480 cm-1; patients with greater intensities displayed the shorter overall survival after the debulking surgery. The SERS signals were eliminated by topically applied monobromobimane that breaks sulfane-sulfur bonds of polysulfides to result in formation of sulfodibimane which was detected at 580 cm-1, manifesting the presence of polysulfides in cancer tissues. CCC-derived cancer cell lines in culture were resistant against cisplatin, but treatment with ambroxol, an expectorant degrading polysulfides, renders the cells CDDP-susceptible. Co-administration of ambroxol with cisplatin significantly suppressed growth of cancer xenografts in nude mice. Furthermore, polysulfides, but neither glutathione nor hypotaurine, attenuated cisplatin-induced disturbance of DNA supercoiling. Polysulfide detection by on-tissue SERS thus enables to predict prognosis of cisplatin-based chemotherapy. The current findings suggest polysulfide degradation as a stratagem unlocking cisplatin chemoresistance.

DOI： 10.1016/j.redox.2021.101926

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1002/osi2.1103

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/osi2.1103

記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：(公社)日本薬学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Prognosis plays a vital role in head and neck squamous cell carcinoma (HNSCC) patient management and decision-making. This study aimed to identify the role of BP180 as a prognostic factor in HNSCC. PATIENTS AND METHODS: Protein expression of bullous pemphigoid antigen II (BP180) was verified by immunohistochemistry (IHC) in a tissue microarray study of 202 cases. RESULTS: IHC analysis revealed that protein expression of BP180 among HNSCC patients differed significantly in the presence and absence of neural invasion, and according to T status in laryngeal and pharyngeal cancer subgroups. Overall survival and multivariate analysis showed that positive BP180-IHC and advanced clinical stage were significant independent positive predictors of mortality in HNSCC patients. In addition, in the oral cancer subgroup, independent positive predictors were positive BP180-IHC, advanced N status and neural invasion. In laryngeal and pharyngeal cancer subgroups, predictors were positive BP180-IHC and advanced clinical stage. CONCLUSION: BP180 is a prognostic factor in head and neck squamous cell carcinoma.

DOI： 10.21873/anticanres.14867

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記述言語：日本語   出版者・発行元：(一社)日本泌尿器科学会総会事務局  

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記述言語：英語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Apolipoprotein A2-ATQ/AT (apoA2-ATQ/AT) has been identified as a minimally invasive biomarker for detecting pancreatic cancer (PC) and high-risk (HR) individuals for PC. To establish an efficient enrichment strategy for HR, we carried out a plasma apoA2-ATQ/AT level-based prospective screening study among the general population. The subjects for the screening study were recruited at six medical check-up facilities in Japan between October 2015 and January 2017. We evaluated the positive predictive value (PPV) of the plasma apoA2-ATQ/AT level of ≤35 μg/mL for detecting PC and HR. Furthermore, we prospectively confirmed its diagnostic accuracy with another post-diagnosis population in a cross-sectional study. We enrolled 5120 subjects in experimental screening, with 84 subjects (1.3%) showing positive results for apoA2-ATQ/AT. Pancreatic abnormalities were recognized in 26 of the 84 subjects from imaging examinations. Pancreatic abnormalities detected included 1 PC and 15 HR abnormalities, such as cystic lesions including intraductal papillary mucinous neoplasm. The PPV of apoA2-ATQ/AT for detecting PC and HR was 33.3%. Moreover, a combination study with another cross-sectional study revealed that the area under the curve for apoA2-ATQ/AT to distinguish PC from healthy controls was 0.903. ApoA2-ATQ/AT has the potential to enrich PC and HR by increasing the diagnostic probability before imaging examinations.

DOI： 10.3390/cancers12092625

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記述言語：日本語   出版者・発行元：(公社)日本生化学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pancreatic cancer (PC) is among the most lethal malignancies due to an often delayed and difficult initial diagnosis. Therefore, the development of a novel, early stage, diagnostic PC marker in liquid biopsies is of great significance. In this study, we analyzed the differential glycomic profiling of extracellular vesicles (EVs) derived from serum (two cohorts including 117 PC patients and 98 normal controls) using lectin microarray. The glyco-candidates of PC-specific EVs were quantified using a high-sensitive exosome-counting system, ExoCounter. An absolute quantification system for altered glycan-containing EVs elevated in PC serum was established. EVs recognized by O-glycan-binding lectins ABA or ACA were identified as candidate markers by lectin microarray. Quantitative analyses using ExoCounter revealed that the ABA- or ACA-positive EVs were significantly increased in the culture of PC cell lines or in the serum of PC patients including carbohydrate antigen 19-9 negative patients with high area under curve values. The elevated numbers of EVs in PC serum returned to normal levels after pancreatectomy. Histological examination confirmed that the tumors stained with ABA/ACA. These specific EVs with O-glycans recognized by ABA/ACA are elevated in PC sera and can act as potential biomarkers in a liquid biopsy for PC patients screening.

DOI： 10.3390/cancers12092469

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: The fact that low concentrations of high-density lipoprotein cholesterol are associated with the risk of cardiovascular disease is well known, but high-density lipoprotein metabolism has not been fully understood. Apolipoprotein A2 (ApoA2) is the second-most dominant apolipoprotein of high-density lipoprotein. We tested the hypothesis that ApoA2 isoforms are inversely associated with myocardial infarction. METHODS: We measured the plasma levels of three ApoA2 isoforms (ApoA2-ATQ/ATQ, ApoA2-ATQ/AT, ApoA2-AT/AT) in nested case-control study samples of 1:2 from the Japan Public Health-Center-based Study (JPHC Study): 106 myocardial infarction incidence cases and 212 controls. RESULTS: ApoA2-AT/AT was inversely associated with risk of myocardial infarction, in a matched model (OR, 2.78; 95% CI, 1.26-6.09 for lowest compared with the highest quartile), but its association was attenuated after adjustment for smoking only (OR=2.13; 95% CI, 0.91-4.97) or drinking only (OR=2.07; 0.91-4.74), and the multivariable OR was 1.20 (95% CI, 0.41-3.57). Neither ApoA2-ATQ/ATQ nor ApoA2-ATQ/AT was associated with the risk of myocardial infarction. CONCLUSIONS: Our nested case-control study did not show a significant association of ApoA2 isoforms with a risk of myocardial infarction.

DOI： 10.5551/jat.56218

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pancreatic cancer remains one of the deadliest cancers worldwide, and it is typically diagnosed late, with a poor prognosis. Early detection is the most important underlying factor for improving the prognosis of pancreatic cancer patients. One of the most effective strategies for detecting cancers at an early stage is screening of the general population. However, because of the low incidence of pancreatic cancer in the general population, the stratification of subjects who need to undergo further examinations by invasive and expensive modalities is important. Therefore, minimally invasive modalities involving biomarkers and imaging techniques that would facilitate the early detection of pancreatic cancer are highly needed. Multiple types of new blood biomarkers have recently been developed, including unique post-translational modifications of circulating proteins, circulating exosomes, microRNAs, and circulating tumor DNA. We previously reported that circulating apolipoprotein A2 undergoes unique processing in the bloodstream of patients with pancreatic cancer and its precancerous lesions. Additionally, we recently demonstrated a new method for measuring pancreatic proton density in the fat fraction using a fat-water magnetic resonance imaging technique that reflects pancreatic steatosis. In this review, we describe recent developments in potential biomarkers and imaging modalities for the early detection and risk stratification of pancreatic cancer, and we discuss current strategies for implementing screening programs for pancreatic cancer.

DOI： 10.3390/cancers12071965

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The comprehensive analysis of biological and clinical aspects of circulating tumor cells (CTCs) has attracted interest as a means of enabling non-invasive, real-time monitoring of cancer patients and enhancing our fundamental understanding of tumor metastasis. However, CTC populations are extremely small when compared to other cell populations in the blood, limiting our comprehension of CTC biology and their clinical utility. Recently developed proteomic and genomic techniques that require only a small amount of sample have attracted much interest and expanded the potential utility of CTCs. Cancer heterogeneity, including specific mutations, greatly impacts disease diagnosis and the choice of available therapeutic strategies. The CTC population consists primarily of cancer stem cells, and CTC subpopulations are thought to undergo epithelial-mesenchymal transition during dissemination. To better characterize tumor cell populations, we demonstrated that changes in genomic profiles identified via next-generation sequencing of liquid biopsy samples could be expanded upon to increase sensitivity without decreasing specificity by using a combination of assays with CTCs and circulating tumor DNA. To enhance our understanding of CTC biology, we developed a metabolome analysis method applicable to single CTCs. Here, we review-omics studies related to CTC analysis and discuss various clinical and biological issues related to CTCs.

DOI： 10.3390/cancers12051135

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Most patients with hormone receptor (HR)-positive, human epidermal growth factor receptor type 2 (HER2)-negative breast cancer can be cured by surgery and endocrine therapy, but a significant proportion suffer recurrences. Actinin-4 is associated with cancer invasion and metastasis, and its genetic alteration may be used for breast cancer prognostication. METHODS: The copy number of the actinin-4 (ACTN4) gene was determined by fluorescence in situ hybridisation (FISH) in two independent cohorts totalling 597 patients (336 from Japan and 261 from the USA) with HR-positive, HER2-negative, node-negative breast cancer. RESULTS: In the Japanese cohort, multivariate analysis revealed that a copy number increase (CNI) of ACTN4 was an independent factor associated with high risks of recurrence (P = 0.01; hazard ratio (HR), 2.95) and breast cancer death (P = 0.014; HR, 4.27). The prognostic significance of ACTN4 CNI was validated in the US cohort, where it was the sole prognostic factor significantly associated with high risks of recurrence (P = 0.04; HR, 2.73) and death (P = 0.016; HR, 4.01). CONCLUSIONS: Copy number analysis of a single gene, ACTN4, can identify early-stage luminal breast cancer patients with a distinct outcome. Such high-risk patients may benefit from adjuvant chemotherapy.

DOI： 10.1038/s41416-020-0821-y

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記述言語：日本語   出版者・発行元：医学図書出版(株)  

膵癌早期発見のためには高リスク保因者を抽出し、サーベイランスを行うことが効率的である。膵癌バイオマーカーにおいても、検診への応用を考えた場合には、膵癌のみならず高リスク保因者も効率的に検出するバイオマーカーが望ましいと考えられる。われわれはアポリポ蛋白A2(apoA2)アイソフォームが膵癌とそのリスク疾患に対して有力なバイオマーカーになり得ることを報告してきた。apoA2アイソフォームは膵外分泌能に関連すると考えられるユニークな膵バイオマーカーで、これまで着実に検証を進め、現在は前向き検診研究によってその有用性を検討している段階である。臨床においては10mm以下膵癌の診断機会が増え長期予後が期待できる症例が増加しつつあり、膵癌バイオマーカーにおいても真の目標である効率的な膵癌死亡率の減少をより強く意識した研究開発が期待される。(著者抄録)

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記述言語：日本語   出版者・発行元：(公社)日本薬学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We established an ultrasensitive method for identifying multiple enzymes in biological samples by using a multiplexed microdevice-based single-molecule enzymatic assay. We used a paradigm in which we "count" the number of enzyme molecules by profiling their single enzyme activity characteristics toward multiple substrates. In this proof-of-concept study of the single enzyme activity-based protein profiling (SEAP), we were able to detect the activities of various phosphoric ester-hydrolyzing enzymes such as alkaline phosphatases, tyrosine phosphatases, and ectonucleotide pyrophosphatases in blood samples at the single-molecule level and in a subtype-discriminating manner, demonstrating its potential usefulness for the diagnosis of diseases based on ultrasensitive detection of enzymes.

DOI： 10.1126/sciadv.aay0888

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掲載種別：研究論文（学術雑誌）   出版者・発行元：American Association for the Advancement of Science (AAAS)  

We established an ultrasensitive method for identifying multiple enzymes in biological samples by using a multiplexed microdevice-based single-molecule enzymatic assay. We used a paradigm in which we “count” the number of enzyme molecules by profiling their single enzyme activity characteristics toward multiple substrates. In this proof-of-concept study of the single enzyme activity–based protein profiling (SEAP), we were able to detect the activities of various phosphoric ester–hydrolyzing enzymes such as alkaline phosphatases, tyrosine phosphatases, and ectonucleotide pyrophosphatases in blood samples at the single-molecule level and in a subtype-discriminating manner, demonstrating its potential usefulness for the diagnosis of diseases based on ultrasensitive detection of enzymes.

DOI： 10.1126/sciadv.aay0888

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction: For pathological diagnosis of pancreatic neuroendocrine neoplasms (pNENs) the routinely used immunohistochemical markers are chromogranin A (CgA) and synaptophysin (Syn). Their ability as prognostic markers is not well established. A splice variant of actinin-4 (Actn-4sv) was recently found to be an excellent biomarker of neuroendocrine neoplasms of the lung. We aimed to investigate the expression of Actn-4sv in pNENs and evaluate its quality as a biomarker of pNENs. Methods: Paraffin-embedded and frozen tissues specimens from 122 pNENs were analyzed. Western blots were performed to prove and compare the relative amount of Actn-4sv expression in pNENs tissue homogenates. For comparison pancreatic ductal adenocarcinoma (PDAC) and normal pancreatic tissues were analyzed in parallel. Immunohistochemistry (IHC) of paraffin sections of pNENs for Actn-4sv were performed and compared to the classic neuroendocrine markers CgA and Syn. Correlations were calculated between the staining intensity and distribution of Actn-4sv and staging, grading and afflicted lymph nodes respectively. Results: Actn-4sv was expressed in 88.5% (108/122) of pNENs, but not in normal pancreatic tissues (0/14) or PDAC (0/14). Compared to CgA and Syn, Actn-4sv was not detectable in islet cells of the normal pancreas. Staining intensity of Actn-4sv on pNENs negatively correlated to the histological grading (Spearman r=-0.4990, p<0.0001) and staging (r = -0.2581, p = 0.0041) but no correlation to afflicted lymph nodes was found. A significantly better overall survival was observed for pNEN patients with higher expression of Actn-4sv (hazard ratio 2.7; log-rank test p= 0.0349). Conclusions: The expression of Actn-4sv may be an important prognostic factor for patients with pNENs. Its expression correlates with the grading and staging of the tumors.

DOI： 10.7150/jca.37503

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記述言語：英語  

DOI： 10.21037/atm.2019.09.161

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：(公社)日本生化学会  

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記述言語：日本語   出版者・発行元：日本電気泳動学会  

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/14737159.2019.1643718

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/cas.14092

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recently, there has been increased attention on the analysis of circulating tumor cells (CTCs), also known as liquid biopsy, owing to its potential benefits in cancer diagnosis and treatment. Circulating tumor cells are released from primary tumor lesions into the blood stream and eventually metastasize to distant body organs. However, a major hurdle with CTC analysis is their natural scarcity. Existing methods lack sensitivity, specificity, or reproducibility required in CTC characterization and detection. Here, we report untargeted molecular profiling of single CTCs obtained from gastric cancer and colorectal cancer patients, using live single cell mass spectrometry integrated with microfluidics-based cell enrichment techniques. Using this approach, we showed the difference in the metabolomic profile between CTCs originating from different cancer groups. Moreover, potential biomarkers were putatively annotated to be specific to each cancer type.

DOI： 10.1111/cas.13915

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The survival times of patients with advanced colorectal cancer (CRC) have increased due to the introduction of chemotherapy involving irinotecan and cetuximab. However, further studies are required on the effective pretreatment methods for identifying patients with CRC who would respond to particular treatments. The aim of the present study was to identify biomarkers for predicting the efficacy of chemotherapy for CRC. A total of 123 serum samples were collected from 31 patients with CRC just prior to each of the first four rounds of chemotherapy. Serum metabolome analysis was performed using a multiplatform metabolomics system, and univariate Cox regression hazards analysis of the time to disease progression was conducted. Octanoic acid and 1,5-anhydro-D-glucitol were identified as biomarker candidates. In addition, the serum level of octanoic acid was indicated to be significantly associated with the time to disease progression (hazard ratio, 3.3; 95% confidence interval, 1.099-11.840; P=0.033). The serum levels of fatty acids, in particular polyunsaturated fatty acids, tended to be downregulated in the partial response group. The findings of the present study suggest that the serum level of octanoic acid may serve as a useful predictor for the prognosis of CRC.

DOI： 10.3892/ol.2018.9731

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掲載種別：研究論文（学術雑誌）  

© 2019 International Institute of Anticancer Research. All Rights Reserved. Background/Aim: Neoadjuvant chemoradiotherapy has side-effects that adversely affect patients' quality of life. The aim of this study was to identify serum metabolite biomarkers that might be used to predict the side-effects of neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma (ESCC). Patients and Methods: Metabolomic analysis of serum samples from 26 patients with ESCC that were collected before neoadjuvant chemoradiotherapy was performed. The metabolites associated with hematological toxicity or nephrotoxicity were evaluated. Results: Serum levels of glutaric acid, glucuronic acid, and cystine were significantly higher in hematological toxicity, and phosphatidylcholines and phosphatidylethanolamines exhibited a tendency to be higher in those with hematological toxicity. The serum level of pyruvic acid was significantly lower in nephrotoxicity, and lysophosphatidylcholines and lysophosphatidylethanolamines tended to be lower in those with nephrotoxicity. Conclusion: Our study found that serum levels of some metabolites differed significantly between patients with and without hematological or renal side-effects. These metabolites may be useful biomarkers for predicting hematological toxicity or nephrotoxicity after neoadjuvant chemoradiotherapy for ESCC.

DOI： 10.21873/anticanres.13143

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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DOI： 10.1248/bpb.b19-00395

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3892/ijo.2018.4581

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DOI： 10.1002/ijc.31900

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   掲載種別：研究論文（その他学術会議資料等）  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.bbrc.2018.02.170

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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掲載種別：研究論文（学術雑誌）  

DOI： 10.2217/bmm-2017-0449

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier B.V.  

The standard therapeutic strategy recommended for locally advanced pancreatic cancer (LAPC) is typically chemotherapy or chemoradiotherapy (CRT). Although the clinical benefit of chemotherapy alone versus CRT for LAPC has been compared in a number of clinical trials, the optimal therapy for LAPC remains unclear. Moreover, the clinical benefit derived from treatment in each clinical trial is a matter of controversy, and the superiority of one treatment over another has yet to be definitively demonstrated. The poor outcomes seen among patients with LAPC owe largely to the emergence of metastatic disease
therefore, accurately evaluating occult distant metastasis before choosing a therapeutic strategy could be expected to help stratify patients with LAPC into the most appropriate treatment regimen, namely local control or systemic therapy. In 1998, we identified the actinin-4 gene (ACTN4) as an actin-binding protein and showed its molecular mechanisms had clinical implications for cancer metastasis. We also identified ACTN4 gene amplification in pancreatic, ovarian, and salivary gland cancer, and demonstrated its utility as a strong prognostic biomarker for stage I lung adenocarcinoma in patients who had never received chemotherapy. Moreover, we recently reported that ACTN4 gene amplification could be a useful biomarker for predicting the efficacy of CRT for LAPC. In the present review, we summarize current knowledge regarding therapeutic strategies for LAPC and discuss the potential development of personalized medicine using ACTN4 measurement for patients with LAPC.

DOI： 10.1016/j.pan.2018.06.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：IMPACT JOURNALS LLC  

Background: The prognostic significance of peripheral immune status in patients with advanced gastric cancer (AGC) remains unclear.
Results: From July 2013 through December 2014, 37 patients were enrolled. Among patients with 25 subsets of immune cells, patients in the high group of granulocytic myeloid-derived suppressor cells (Gr-MDSCs) showed significantly shorter progression-free survival (PFS) than those in the low group (3.98 vs. 8.78 months; hazards ratio (HR), 2.61; p = 0.01). In multivariate analysis, the high Gr-MDSCs value was also associated with shorter PFS (HR, 4.60; 95% confidence interval (CI), 1.79-11.8; p = 0.001). Although significant difference was not found in univariate analysis, the high Gr-MDSCs group was associated with shorter overall survival (OS) (HR, 2.89; 95% CI, 1.23-6.80; p = 0.015) in multivariate analysis.
Materials and Methods: In this explorative prospective study, peripheral blood samples were collected from AGC patients before initiating first-line cisplatin-based chemotherapy (S-1 + cisplatin or S-1 + cisplatin + docetaxel). Peripheral blood mononuclear cells were analyzed for 25 immune subsets by multicolor flow cytometry. PFS and OS were compared between the patients divided into high and low (&gt;= and &lt; median, respectively) groups based on the median value for each immune cell subset.
Conclusions: The peripheral immune status of Gr-MDSCs appears to affect the prognosis in AGC. Further research is needed to confirm the clinical value of the level of circulating Gr-MDSCs as a prognostic and/or predictive marker in AGC.

DOI： 10.18632/oncotarget.18297

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER GMBH, URBAN & FISCHER VERLAG  

Invadopodia are ventral membrane protrusions formed by cancer cells that degrade the extracellular matrix (ECM) during tumor invasion and metastasis. Formation of invadopodia is initiated by the assembly of actin filaments (F-actin) that results from the coordinated activation of several actin regulatory proteins. Actinin-1 and actinin-4 are actin bundling proteins expressed in non-muscle cells and actinin-4 is preferentially associated with malignant phenotypes of carcinoma cells. In this study, we investigated the role of actinin-1 and -4 in invadopodia formation. Expression of both actinin-1 and -4 tended to be higher in invasive and metastatic breast carcinoma cell lines than in non-invasive ones. Immunofluorescence analysis revealed that actinin-1 and -4 colocalized at core actin structures of invadopodia. Time-lapse imaging showed that appearance of both actinins at invadopodia is concomitant with the assembly of F-actin. Knockdown of either actinin-1 or actinin-4 suppressed the formation of invadopodia and degradation of the ECM by carcinoma cells. Interestingly, over expression of actinin-4, but not actinin-1, significantly promoted the formation of invadopodia and this activity required the actin binding domains and the unique N-terminal motif that exists only in actinin-4. These results demonstrate that both actinin-1 and actinin-4 participate in the assembly of F-actin at invadopodia. Additionally, actinin-4 may have a selective advantage in accelerating invadopodia-mediated invasion of carcinoma cells.

DOI： 10.1016/j.ejcb.2017.07.005

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記述言語：日本語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：FUTURE MEDICINE LTD  

Aim: Although several clinical trials demonstrated the benefits of platinum-combination adjuvant chemotherapy for stage II-IIIA lung adenocarcinoma, predictive biomarkers for the efficacy of such therapy have not yet been identified. We evaluated protein overexpression of actinin-4 as a predictive biomarker of the efficacy of adjuvant chemotherapy in resected lung adenocarcinoma. Materials & methods: We measured actinin-4 protein levels in patients with completely resected stage II-IIIA lung adenocarcinoma using immunohistochemistry and then retrospectively compared survival between adjuvant chemotherapy and observation groups. Results: A total of 148 eligible patients were classified into actinin-4 positive or negative cases by immunohistochemistry. In the former, patients with adjuvant chemotherapy survived significantly longer than those with observation (hazard ratio [HR]: 0.307; p = 0.028). But, no significant survival benefit was noted with adjuvant chemotherapy (HR: 0.926; p = 0.876) in the latter. Conclusion: This marker could predict the efficacy of adjuvant chemotherapy for resected lung adenocarcinoma patients.

DOI： 10.2217/bmm-2017-0150

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CHURCHILL LIVINGSTONE  

Despite complete resection of the early stage of oral tongue cancer by partial glossectomy, late cervical lymph node metastasis is frequently observed. Gene amplification of ACTN4 (protein name: actinin-4) is closely associated with the metastatic potential of various cancers. This retrospective study was performed to demonstrate the potential usefulness of ACTN4 gene amplification as a prognostic biomarker in patients with stage I/II oral tongue cancer. Fifty-four patients with stage I/II oral tongue cancer were enrolled retrospectively, in accordance with the reporting recommendations for tumour marker prognostic studies (REMARK). guidelines. The copy number of ACTN4 and the protein expression of actinin-4 were evaluated by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), respectively. The overall survival time of patients with gene amplification of ACTN4 was significantly shorter than that of patients without gene amplification (P = 0.0010, log-rank test). Gene amplification of ACTN4 was a significant independent risk factor for death in patients with stage I/II oral tongue cancer (hazard ratio 6.08, 95% confidence interval 1.66-22.27). Gene amplification of AETN4 is a potential prognostic biomarker for overall survival in oral tongue cancer.

DOI： 10.1016/j.ijom.2017.03.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Background: To improve prognosis of pancreatic cancer (PC) patients, the discovery of more reliable biomarkers for the early detection is desired.
Methods: Blood samples were collected by 2 independent groups. The 1st set was included 55 early PC and 58 healthy volunteers (HV), and the 2nd set was included 16 PC and 16 HV. The 16 targeted metabolites were quantitatively analyzed by gas chromatography/tandem mass spectrometry together with their corresponding stable isotopes. In the 1st set, the levels of these metabolites were evaluated, and diagnostic models were constructed via multivariate logistic regression analysis, leading to validation using the 2nd set.
Results: In the 1st set, model X consisting of 4 candidates based on our previous report possessed higher sensitivity (74.1%) than carbohydrate antigen 19-9 (CA19-9). Model Y, consisting of 2 metabolites newly selected from 16 metabolites via stepwise method possessed higher sensitivity (70.4%) than CA19-9. Furthermore, combining model Y with CA19-9 increased its sensitivity (90.7%) and specificity (89.5%). In the 2nd set, combining model Y with CA19-9 displayed high sensitivity (81.3%) and specificity (93.8%). In particular, it displayed very high sensitivity (100%) for resectable PC.
Conclusions: Quantitative analysis confirmed that metabolomics-based diagnostic methods are useful for detecting PC early. (C) 2017 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.cca.2017.02.011

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器外科学会  

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記述言語：日本語   出版者・発行元：科学評論社  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：英語   出版者・発行元：Oxford University Press  

Background: Sorafenib is a multikinase-tyrosine kinase inhibitor commonly used in a variety of cancers. There are concerns about the increased risk of serious adverse events (SAEs) and fatal adverse events (FAEs) with sorafenib. We performed an upto- date meta-analysis of all phase 3 randomized controlled trials (RCTs) of sorafenib to quantify the increased risk of SAEs and FAEs. Patients and methods: We carried out a systematic search of electronic databases for studies published from inception to February 2016 without any restrictions. Eligibility criteria included phase 3 RCTs of solid tumors comparing sorafenib, alone or in combination with nontargeted chemotherapy (Sorafenib arm) versus placebo or nontargeted chemotherapy (control arm). Data on SAEs and FAEs for both the arms were extracted from each study and pooled to determine the overall incidence, relative risks (RRs) and 95% Confidence Intervals (CIs). Results: Of 471 studies identified, a total of 12 phase 3 RCTs involving 6797 solid cancer patients comparing sorafenib with control met the eligibility criteria and were included. The overall incidence of SAEs and FAEs with sorafenib were 26.4% (95% CI, 18.0- 36.9%) and 1.3% (95% CI: 0.8-2.2%), respectively. Compared with control, sorafenib use significantly increased the risk of both SAEs (RR: 1.49, 95% CI: 1.18-1.89, P=0.001) and FAEs (RR: 1.82, 95% CI: 1.05-3.14, P=0.033). This association varied significantly with cancer types (P &lt
0.001) and approval status (P=0.012) for SAEs but no evidence of heterogeneity was found for FAEs. Conclusions: This meta-analysis of phase 3 RCTs demonstrates an increased risk of both SAEs and FAEs with sorafenib use in adult patients with solid cancers. This quantification of increased risks of SAEs and FAEs will be important in considering the trade-off of sorafenib treatment during shared decision-making.

DOI： 10.1093/annonc/mdw549

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：英語   出版者・発行元：FUTURE MEDICINE LTD  

Given the low incidence of pancreatic cancer in the general population, screening of pancreatic cancer in the general population using invasive modalities is not feasible. Combination of invasive screening with noninvasive biomarkers for pancreatic cancer and its precancerous lesions has the potential to reduce mortality due to pancreatic cancer. In this review, we focus on biomarkers found in the blood that can indicate early-stage pancreatic cancer, and we discuss current strategies for screening for pancreatic cancer. We recently identified a unique alteration in apolipoprotein A2 isoforms in pancreatic cancer and its precancerous lesions, and we describe its clinical usefulness as a potential biomarker for the early detection and risk stratification of pancreatic cancer.

DOI： 10.2217/bmm-2016-0209

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

The clinical benefit of combination treatment with panitumumab and bevacizumab (PB) based on bevacizumab beyond progression (BBP) after the failure of second-line chemotherapy remains unclear. We assessed the tolerability and efficacy of PB as BBP in Japanese patients with metastatic colorectal cancer (mCRC).This phase I study comprised two parts: (1) PB part to estimate the recommended PB dose, (2) CPB part to investigate the safety of PB with irinotecan (CPB). Three panitumumab doses (4, 5, and 6 mg/kg at Levels -1, 0 and 1, respectively) were set for the PB part, starting with Level 0. Bevacizumab was administered at a fixed dose of 5 mg/kg, regardless of panitumumab dose levels. All drugs were administered on day 1 and repeated every 2 weeks.No dose-limiting toxicities were observed at Levels 0 (n = 3) and 1 (n = 3) for the PB part, determining the recommended dose as Level 1. During the whole treatment course at Level 1, grade 3 acneiform rash was observed in two patients with a partial response. For six patients (irinotecan biweekly, 150 mg/m(2) n = 3, 120 mg/m(2) n = 3) enrolled in the CPB part, grade 3 toxicities were leukopenia/neutropenia (n = 1), mucositis (n = 1), diarrhea (n = 1), rash acneiform (n = 1) and thromboembolic event (n = 1), and two of six patients achieved partial responses.Recommended doses for the PB regimen in mCRC were panitumumab 6 mg/kg and bevacizumab 5 mg/kg. PB and CPB showed manageable toxicities in KRAS wild-type patients previously managed with standard treatment, including bevacizumab.

DOI： 10.1007/s00280-016-3111-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Pancreatic cancer is one of the most lethal tumors, and reliable detection of early-stage pancreatic cancer and risk diseases for pancreatic cancer is essential to improve the prognosis. As 260 genes were previously reported to be upregulated in invasive ductal adenocarcinoma of pancreas (IDACP) cells, quantification of the corresponding proteins in plasma might be useful for IDACP diagnosis. Therefore, the purpose of the present study was to identify plasma biomarkers for early detection of IDACP by using two proteomics strategies: antibody-based proteomics and liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics. Among the 260 genes, we focused on 130 encoded proteins with known function for which antibodies were available. Twenty-three proteins showed values of the area under the curve (AUC) of more than 0.8 in receiver operating characteristic (ROC) analysis of reverse-phase protein array (RPPA) data of IDACP patients compared with healthy controls, and these proteins were selected as biomarker candidates. We then used our high-throughput selected reaction monitoring or multiple reaction monitoring (SRM/MRM) methodology, together with an automated sample preparation system, micro LC and auto analysis system, to quantify these candidate proteins in plasma from healthy controls and IDACP patients on a large scale. The results revealed that insulin-like growth factor- binding protein (IGFBP) 2 and IGFBP3 have the ability to discriminate IDACP patients at an early stage from healthy controls, and IGFBP2 appeared to be increased in risk diseases of pancreatic malignancy, such as intraductal papillary mucinous neoplasms (IPMNs). Furthermore, diagnosis of IDACP using the combination of carbohydrate antigen 19-9 (CA19-9), IGFBP2 and IGFBP3 is significantly more effective than CA19-9 alone. This suggests that IGFBP2 and IGFBP3 may serve as compensatory biomarkers for CA19-9. Early diagnosis with this marker combination may improve the prognosis of IDACP patients.

DOI： 10.1371/journal.pone.0161009

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DOI： 10.1200/JCO.2016.34.15_suppl.e20003

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：IMPACT JOURNALS LLC  

Although several clinical trials have demonstrated the benefits of platinum-combined adjuvant chemotherapy for resected non-small cell lung cancer (NSCLC), predictive biomarkers for the efficacy of such therapy have not yet been identified. Selection of patients with high metastatic ability in the early stage of non-small cell lung cancer (NSCLC) has the potential to predict clinical benefit of adjuvant chemotherapy (ADJ).
In order to develop a predictive biomarker for efficacy of ADJ, we reanalyzed patient data using a public database enrolled by JBR. 10, which was a clinical trial to probe the clinical benefits of ADJ in stage-IB/II patients with NSCLC. The patients who were enrolled by JBR. 10 were classified into 2 subgroups according to expression of the ACTN4 transcript: ACTN4 positive (ACTN4 (+)) and ACTN4 negative (ACTN4 (-)). In the ACTN4 (+) group, overall survival (OS) was significantly higher in the ADJ subgroup compared with the observation subgroup (OBS), indicating a significant survival benefit of ADJ. However, no difference in OS was found between ADJ and OBS groups in ACTN4 (-). Although ACTN4 expression level did not correlate with the chemosensitivity of cancer cell lines for cytotoxic drugs, the metastatic potential of A549 lung adenocarcinoma cells was significantly reduced by ACTN4 shRNA in in vitro assays and in an animal transplantation model. The clinical and preclinical data suggested that ACTN4 is a potential predictive biomarker for efficacy of ADJ in stage-IB/II patients with NSCLC, by reflecting the metastatic potential of tumor cells.

DOI： 10.18632/oncotarget.8890

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

We recently reported that circulating apolipoprotein AII (apoAII) isoforms apoAII-ATQ/AT (C-terminal truncations of the apoAII homo-dimer) decline significantly in pancreatic cancer and thus might serve as plasma biomarkers for the early detection of this disease. We report here the development of novel enzyme-linked immunosorbent assays (ELISAs) for measurement of apoAII-ATQ/AT and their clinical applicability for early detection of pancreatic cancer. Plasma and serum concentrations of apoAII-ATQ/AT were measured in three independent cohorts, which comprised healthy control subjects and patients with pancreatic cancer and gastroenterologic diseases (n = 1156). These cohorts included 151 cases of stage I/II pancreatic cancer. ApoAII-ATQ/AT not only distinguished the early stages of pancreatic cancer from healthy controls but also identified patients at high risk for pancreatic malignancy. AUC values of apoAII-ATQ/AT to detect early stage pancreatic cancer were higher than those of CA19-9 in all independent cohorts. ApoAII-ATQ/AT is a potential biomarker for screening patients for the early stage of pancreatic cancer and identifying patients at risk for pancreatic malignancy (161 words).

DOI： 10.1038/srep15921

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記述言語：英語   出版者・発行元：BIOMED CENTRAL LTD  

Invasion and metastasis are malignant phenotypes in cancer that lead to patient death. Cell motility is involved in these processes. In 1998, we identified overexpression of the actin-bundling protein actinin-4 in several types of cancer. Protein expression of actinin-4 is closely associated with the invasive phenotypes of cancers. Actinin-4 is predominantly expressed in the cellular protrusions that stimulate the invasive phenotype in cancer cells and is essential for formation of cellular protrusions such as filopodia and lamellipodia. ACTN4 (gene name encoding actinin-4 protein) is located on human chromosome 19q. ACTN4 amplification is frequently observed in patients with carcinomas of the pancreas, ovary, lung, and salivary gland, and patients with ACTN4 amplifications have worse outcomes than patients without amplification. In addition, nuclear distribution of actinin-4 is frequently observed in small cell lung, breast, and ovarian cancer. Actinin-4, when expressed in cancer cell nuclei, functions as a transcriptional co-activator. In this review, we summarize recent developments regarding the biological roles of actinin-4 in cancer invasion.

DOI： 10.1186/s13578-015-0031-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：INT INST ANTICANCER RESEARCH  

Background: The alternatively spliced actinin-4 variant (ACTN4va) is expressed in small-cell lung cancer (SCLC) and is thought to be a potential diagnostic marker. However, ACTN4va expression has not been examined in transbronchial biopsy specimens. Materials and Methods: We retrospectively examined the relationship between ACTN4va expression, clinical factors and survival in 104 consecutive newly-diagnosed SCLC patients. Results: Of the 104 screened cases, 83 (median age=69 years; transbronchial biopsy, 71) were included in our study. Survival was significantly different in the group with no distant metastasis (1996 vs. 422 days, respectively; p=0.000115) but was not significantly different with regard to ACTN4va expression in the group with distant metastasis (293 vs. 254 days, respectively; p=0.678). Conclusion: ACTN4va expression was identifiable in small biopsy samples. ACTN4va expression was also significantly related to distant metastasis and could stratify SCLC patients according to prognosis.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Background: Several clinical trials have compared chemotherapy alone and chemoradiotherapy (CRT) for locally advanced pancreatic cancer (LAPC) treatment. However, predictive biomarkers for optimal therapy of LAPC remain to be identified. We retrospectively estimated amplification of the ACTN4 gene to determine its usefulness as a predictive biomarker for LAPC.
Methods: The copy number of ACTN4 in 91 biopsy specimens of LAPC before treatment was evaluated using fluorescence in situ hybridisation (FISH).
Results: There were no statistically significant differences in overall survival (OS) or progression-free survival (PFS) of LAPC between patients treated with chemotherapy alone or with CRT. In a subgroup analysis of patients treated with CRT, patients with a copy number increase (CNI) of ACTN4 had a worse prognosis of OS than those with a normal copy number (NCN) of ACTN4 (P = 0.0005, log-rank test). However, OS in the subgroup treated with chemotherapy alone was not significantly different between patients with a CNI and a NCN of ACTN4. In the patients with a NCN of ACTN4, the median survival time of PFS in CRT-treated patients was longer than that of patients treated with chemotherapy alone (P = 0.049).
Conclusions: The copy number of ACTN4 is a predictive biomarker for CRT of LAPC.

DOI： 10.1038/bjc.2014.623

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Copy number increase (CNI) of ACTN4 has been associated with poor prognosis and metastatic phenotypes in various human carcinomas. To identify a novel prognostic factor for salivary gland carcinoma, we investigated the copy number of ACTN4. We evaluated DNA copy number of ACTN4 in 58 patients with salivary gland carcinoma by using fluorescent in situ hybridization (FISH). CNI of ACTN4 was recognized in 14 of 58 patients (24.1%) with salivary gland carcinoma. The cases with CNI of ACTN4 were closely associated with histological grade (P = 0.047) and vascular invasion (P = 0.033). The patients with CNI of ACTN4 had a significantly worse prognosis than the patients with normal copy number of ACTN4 (P = 0.0005 log-rank test). Univariate analysis by the Cox proportional hazards model showed that histological grade, vascular invasion, and CNI of ACTN4 were independent risk factors for cancer death. Vascular invasion (hazard ratio [HR]: 7.46; 95% confidence interval [CI]: 1.98-28.06) and CNI of ACTN4 (HR: 3.23; 95% CI: 1.08-9.68) remained as risk factors for cancer death in multivariate analysis. Thus, CNI of ACTN4 is a novel indicator for an unfavorable outcome in patients with salivary gland carcinoma.

DOI： 10.1002/cam4.214

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：INT INST ANTICANCER RESEARCH  

Aim: To assess the clinicopathological significance of the histological growth pattern (HGP) and alpha-actinin-4 (ACTN4) expression in thyroid cancer. Patients and Methods: We classified 83 thyroid cancer cases into infiltrative margin (IM) and pushing margin (PM) groups according to peripheral tumor margin contour and immunohistochemically determined ACTN4 expression. Correlations between clinical stage and clinicopathological characteristics were analyzed. Results: IM and high ACTN4 expression were observed in 39% and 49% of cancer cases, respectively. Higher clinical stage was significantly correlated with older age, higher T and N factor, preoperative recurrent laryngeal nerve paralysis (pre-RLNP), IM, and poor prognosis. Patients with stage IV disease had significantly poorer prognosis than those with stages I Ill. On multivariate analysis, older age, pre-RLNP, and IM correlated with higher clinical stages. IM was significantly correlated with high ACTN4 expression. Conclusion: IM, pre-RLNP, and ACTN4 expression could be novel indicators of tumor aggression and prognostic factors of thyroid cancer.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Sorafenib is a multi-kinase inhibitor that has been proven effective for the treatment of unresectable hepatocellular carcinoma (HCC). However, its precise mechanisms of action and resistance have not been well established. We have developed high-density fluorescence reverse-phase protein arrays and used them to determine the status of 180 phosphorylation sites of signaling molecules in the 120 pathways registered in the NCI-Nature curated database in 23 HCC cell lines. Among the 180 signaling nodes, we found that the level of ribosomal protein S6 phosphorylated at serine residue 235/236 (p-RPS6 S235/236) was most significantly correlated with the resistance of HCC cells to sorafenib. The high expression of p-RPS6 S235/236 was confirmed immunohistochemically in biopsy samples obtained from HCC patients who responded poorly to sorafenib. Sorafenib-resistant HCC cells showed constitutive activation of the mammalian target of rapamycin (mTOR) pathway, but whole-exon sequencing of kinase genes revealed no evident alteration in the pathway. p-RPS6 S235/236 is a potential biomarker that predicts unresponsiveness of HCC to sorafenib. The use of mTOR inhibitors may be considered for the treatment of such tumors.

DOI： 10.1074/mcp.M113.033845

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER JAPAN KK  

Actinin-4 is an isoform of nonmuscular alpha-actinin and actin-bundling protein that plays an important role in cancer invasion and metastasis by enhancing cellular motility. Recent studies have revealed an association between several clinicopathological profiles and actinin-4 overexpression in human cancers. In this study, we investigated the immunohistochemical actinin-4 expression in 39 infiltrating gliomas. The specimens included three diffuse astrocytomas, three oligodendrogliomas, one oligoastrocytoma, two anaplastic astrocytomas, four anaplastic oligodendrogliomas, three anaplastic oligoastrocytomas, 17 glioblastomas, four gliosarcomas, and two glioblastomas with oligodendroglial component. All seven World Health Organization (WHO) grade II tumors were negative for actinin-4, whereas 20 of 22 tumors with strong actinin-4 expression were WHO grade IV. Actinin-4 expression was significantly associated with histological grade (P &lt; 0.0001) and proliferative activity measured by Ki-67 staining (P = 0.0045). Notably, actinin-4 expression was more pronounced in high-grade astrocytic tumors than oligodendroglial tumors (P &lt; 0.0001). Additionally, pseudopalisading cells in glioblastoma exhibited stronger actinin-4 expression than the rest, likely reflecting enhanced cellular motility in pseudopalisades. This study is the first to demonstrate significant correlation between actinin-4 expression and tumor grade using clinical glioma samples. Although diagnostic utility of this marker awaits future exploration, actinin-4 may help distinguish between astrocytic and oligodendroglial lines of differentiation.

DOI： 10.1007/s10014-013-0139-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Objective: Osteosarcoma (OS) is the most frequent primary malignant bone tumor in children and young adults. Although the introduction of combined neoadjuvant chemotherapy has significantly prolonged survival, the outcome for OS patients showing a poor response to chemotherapy is still unfavorable. In order to develop new therapeutic approaches, elucidation of the entire molecular pathway regulating OS cell proliferation would be desirable. Methods: MicroRNA (miRNA) are highly conserved noncoding RNA that play important roles in the development and progression of various other cancers. Using miRNA microarrays capable of detecting a known number of 933 miRNA, 108 miRNA were found to be commonly expressed in 24 samples of OS tissue and subjected to a cell proliferation assay. Results: We found that inhibition of 5 let-7 family nniRNA (hsa-let-7a, b, f, g and i) significantly suppressed the proliferation of OS cells. Using a quantitative shotgun proteomics approach, we also found that the let-7 family miRNA regulated the expression of vimentin and serpin H1 proteins. Conclusions: Our present results indicate the involvement of let-7 family miRNA in regulation of the cell proliferation as well as epithelial-mesenchymal transition of OS. Thus, let-7 family miRNA may potentially provide novel targets for the development of therapeutic strategies against OS. (C) 2014 S. Karger AG, Basel

DOI： 10.1159/000357408

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

DOI： 10.11241/jsmtmr.29.2

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その他リンク： http://search.jamas.or.jp/link/ui/2015388672

記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

DOI： 10.11241/jsmtmr.29.67

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その他リンク： http://search.jamas.or.jp/link/ui/2015388706

記述言語：日本語   出版者・発行元：日本プロテオーム学会（日本ヒトプロテオーム機構）  

DOI： 10.14889/jhupo.2014.0.38.0

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

Even if detected at an early stage, a substantial number of lung cancers relapse after curative surgery. However, no method for distinguishing such tumors has yet been established.
The copy number of the actinin-4 (ACTN4) gene was determined by fluorescence in situ hybridization on tissue microarrays comprising 543 surgically resected adenocarcinomas of the lung.
Amplification (an increase in the copy number by &gt;= 2.0 fold) of the ACTN4 gene was detected in two of seven lung adenocarcinoma cell lines and 79 (15%) of 543 cases of pathological stage I-IV lung adenocarcinoma. Multivariate analysis revealed that ACTN4 gene amplification was the most significant independent factor associated with an extremely high risk of death (hazard ratio, 6.78; P = 9.48 x 10(-5), Cox regression analysis) among 290 patients with stage I lung adenocarcinoma. The prognostic significance of ACTN gene amplification was further validated in three independent cohorts totaling 1033 patients.
Amplification of the ACTN4 gene defines a small but substantial subset of patients with stage I lung adenocarcinoma showing a distinct outcome. Such patients require intensive medical attention and might benefit from postoperative adjuvant chemotherapy.

DOI： 10.1093/annonc/mdt293

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

We previously showed that Rab13 and its effector protein, junctional Rab13-binding protein (JRAB)/molecules interacting with CasL-like 2 (MICAL-L2), regulate junctional development by modulating cell adhesion molecule transport and actin cytoskeletal reorganization in epithelial cells. Here, we investigated how JRAB regulates reorganization of the actin cytoskeleton in NIH3T3 fibroblasts, in an attempt to obtain novel insights into the mechanism of JRAB action. To this end, we expressed mutant proteins that adopt a constitutively open or closed state and then examined effect on cellular morphology of the resulting actin cytoskeletal reorganization. Expression of the JRAB Delta CT mutant (constitutively 'closed' state) induced stress fibers, whereas expression of the JRAB Delta CC mutant (constitutively 'open' state) caused cell spreading with membrane ruffles. Next, we identified the proteins involved in JRAB-induced rearrangement of actin cytoskeleton leading to morphological changes. In NIH3T3 cells expressing HA-JRAB Delta CC, filamin, an actin cross-linking protein, coimmunoprecipitated with HA-JRAB Delta CC. Expression of ASB2 induced degradation of all three filamin isoforms and inhibited the JRAB Delta CC-induced cell spreading. Consistent with our previous results, actinin-1/-4 were also immunoprecipitated with HA-JRAB Delta CC. However, actinin-1/-4 have no effect on the cell spreading regulated by JRAB Delta CC. These data suggest that JRAB contributes to the rearrangement of the actin cytoskeleton during cell spreading via filamins.

DOI： 10.1111/gtc.12078

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Salivary gland tumors are relatively rare and morphologically diverse and heterogeneous tumors
therefore, histogenesis-based tumor markers are sorely needed to aid in diagnosing and determining the cell type of origin. SRY-related HMG-box 10 (SOX10) protein is a transcription factor known to be crucial in the specification of the neural crest and maintenance of Schwann cells and melanocytes. In addition, positive expression has also been implicated in the major salivary gland. Here, we examined SOX10 expression in various salivary gland tumors to correlate this expression with myoepithelial markers. Overall, 76 malignant and 14 benign tumors were examined. SOX10 expression clearly delineated two distinct subtypes of human salivary gland tumors
acinic cell carcinomas, adenoid cystic carcinomas, epithelial-myoepithelial carcinomas, myoepithelial carcinomas, and pleomorphic adenomas, including the pleomorphic adenoma component of carcinoma, were SOX10 positive, while salivary duct carcinomas, mucoepidermoid carcinomas, an oncocytic carcinoma, Oncocytomas, and Warthin tumors were SOX10 negative. Also, SOX10 was expressed in solid-type or non-specific morphology salivary gland tumors, but was not expressed in poorly differentiated squamous cell carcinomas. In normal human salivary gland tissue, SOX10 expression was specific to the nuclei of acini and both luminal and abluminal cells of intercalated ducts but not in other sites. Moreover, the murine model suggested that SOX10 continued to be expressed from the developmental stage to adulthood in the acinar and both luminal and abluminal intercalated ducts in the major salivary gland. Thus, SOX10 is a novel marker for diagnosing and understanding the histogenesis of salivary gland tumors. © 2013 USCAP, Inc. All rights reserved.

DOI： 10.1038/modpathol.2013.54

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Preoperative chemoradiotherapy has been shown to improve the outcome of patients with esophageal cancer, but because response to this therapy varies, it is desirable to identify in advance individuals who would be unlikely to benefit, in order to avoid unnecessary adverse drug effects. The serum profiles of 84 cytokines and related proteins were determined in 37 patients with esophageal squamous cell carcinoma who received identical neoadjuvant preoperative chemoradiotherapy regimens and underwent surgical resection. Histological response to this therapy was assessed in surgically resected specimens. The serum soluble interleukin-6 receptor (sIL6R) level was significantly higher in 30 patients who failed to achieve a histological complete response (P = 0.005). Multivariate analysis revealed that the increased level of sIL6R was one of several significant independent predictors of an unfavorable outcome (hazard ratio, 2.87; P = 0.017). The increased level of this cytokine in patients who did not obtain a complete response was reproducibly observed in an independent cohort of 34 patients. Esophageal squamous cell carcinoma patients with an increased serum level of sIL6R are predicted to respond poorly to preoperative chemoradiotherapy, therefore, their exclusion from this treatment may be considered. Persistent systemic inflammation is implicated as a possible mechanism of resistance to this therapy.

DOI： 10.1111/cas.12187

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記述言語：英語   出版者・発行元：OXFORD UNIV PRESS  

Cancer biomarkers for the early detection of malignancies and selection of therapeutic strategies have been requested in the clinical field. Accurate and informative cancer biomarkers hold significant promise for improvements in the early detection of disease and in the selection of the most effective therapeutic strategies. Recently, significant progress in the comprehensive analysis of the human genome, epigenome, transcriptome, proteome and metabolome has led to revolutionary changes in the discovery of cancer biomarkers. The Human Proteome Organization has launched a global Human Proteome Project to map the entire human protein set. The Human Proteome Project research group has focused on three working proteomic pillarsumass spectrometry-based, antibody-based and knowledge-based proteomicsuand each of these technologies is advancing rapidly. In this review, we introduce the proteomic platforms that are currently being used for cancer biomarker discovery, and describe examples of novel cancer biomarkers that were identified with each proteomic technology.

DOI： 10.1093/jjco/hys200

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

High-grade neuroendocrine tumours (HGNTs) of the lung manifest a wide spectrum of clinical behaviour, but no method for predicting their outcome has been established.
We newly established a monoclonal antibody specifically recognizing the product of the alternatively spliced ACTN4 transcript (namely, variant actinin-4), and used it to examine the expression of variant actinin-4 immunohistochemically in a total of 609 surgical specimens of various histological subtypes of lung cancer.
Variant actinin-4 was expressed in 55% (96/176) of HGNTs, but in only 0.8% (3/378) of non-neuroendocrine (NE) lung cancers. The expression of variant actinin-4 was significantly associated with poorer overall survival in HGNT patients (P = 0.00021, log-rank test). Multivariate analysis using the Cox proportional hazards model showed that the expression of variant actinin-4 was the most significant independent negative predictor of survival in HGNT patients (hazard ratio (HR), 2.15; P = 0.00113) after the presence of lymph node metastasis (HR, 2.25; P = 0.00023).
The expression of variant actinin-4 is an independent prognostic factor for patients with HGNTs. This protein has a high affinity for filamentous actin polymers and likely promotes aggressive behaviour of cancer cells. The present clinical findings clearly support this notion.

DOI： 10.1093/annonc/mds215

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記述言語：日本語   出版者・発行元：日本臨床プロテオーム研究会  

DOI： 10.14905/jscp.2013.0_16

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

During epithelial junctional development, both vesicle transport and reorganization of the actin cytoskeleton must be spatiotemporally regulated. Coordination of these cellular functions is especially important, but the precise mechanism remains elusive. Previously, we identified junctional Rab13-binding protein (JRAB)/molecules interacting with CasL-like 2 (MICAL-L2) as an effector of the Rab13 small G protein, and we found that the Rab13-JRAB system may be involved in the formation of cell-cell adhesions via transport of adhesion molecules. Here, we showed that JRAB interacts with two actin-binding proteins, actinin-1 and -4, and filamentous actin via different domains and regulates actin cross-linking and stabilization through these interactions. During epithelial junctional development, JRAB is prominently enriched in the actin bundle at the free border; subsequently, JRAB undergoes a Rab13-dependent conformational change that is required for maturation of cell-cell adhesion sites. These results suggest that Rab13 and JRAB regulate reorganization of the actin cytoskeleton throughout epithelial junctional development from establishment to maturation of cell-cell adhesion.

DOI： 10.1074/jbc.M112.383653

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Background: Among the more common human malignancies, invasive ductal carcinoma of the pancreas has the worst prognosis. The poor outcome seems to be attributable to difficulty in early detection.
Methods: We compared the plasma protein profiles of 112 pancreatic cancer patients with those of 103 sex- and age-matched healthy controls (Cohort 1) using a newly developed matrix-assisted laser desorption/ionization (oMALDI) QqTOF (quadrupole time-of-flight) mass spectrometry (MS) system.
Results: We found that hemi-truncated apolipoprotein AII dimer (ApoAII-2; 17252 m/z), unglycosylated apolipoprotein CIII (ApoCIII-0; 8766 m/z), and their summed value were significantly decreased in the pancreatic cancer patients [P = 1.36 x 10(-21), P = 4.35 x 10(-14), and P = 1.83 x 10(-24) (Mann-Whitney U-test); area-under-curve values of 0.877, 0.798, and 0.903, respectively]. The significance was further validated in a total of 1099 plasma/serum samples, consisting of 2 retrospective cohorts [Cohort 2 (n = 103) and Cohort 3 (n = 163)] and a prospective cohort [Cohort 4 (n = 833)] collected from 8 medical institutions in Japan and Germany.
Conclusions: We have constructed a robust quantitative MS profiling system and used it to validate alterations of modified apolipoproteins in multiple cohorts of patients with pancreatic cancer.

DOI： 10.1371/journal.pone.0046908

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Yamamoto S, Tsuda H, Honda K, Takano M, Tamai S, Imoto I, Inazawa J, Yamada T & Matsubara O ?(2012) Histopathology similar to 60,10731083 ACTN4 gene amplification and actinin-4 protein overexpression drive tumour development and histological progression in a high-grade subset of ovarian clear-cell adenocarcinomas Aims: Actinin-4, encoded by the ACTN4 gene located on chromosome 19q13.2, enhances cell motility by bundling the actin cytoskeleton. We assessed how ACTN4/actinin-4 alterations contribute to the tumorigenesis of ovarian clear-cell adenocarcinomas (CCAs). Methods and results: Fluorescence in-situ hybridization analysis demonstrated that ACTN4 amplification (=4 ACTN4 copies in =40% of cells) occurred in 27 (33%) of 81 CCAs and genomic gains of ACTN4 were associated strongly with immunohistochemical actinin-4 overexpression, poorly differentiated tumour histology and shorter patient survival (all P &lt; 0.05). From the 27 ACTN4-amplified CCAs, 23 tumours with adjacent putative precursor lesions were selected and examined for ACTN4/actinin-4 alterations with respect to their intratumoral heterogeneity. In this selected cohort, none of the precursors lacking cytological atypia exhibited gains of ACTN4 or actinin-4 overexpression; 50% of the atypical endometrioses and 75% of the borderline CCAFs showed low-level gains of ACTN4 and actinin-4 overexpression, respectively. In 12 of 23 ACTN4-amplified CCAs, intratumoral heterogeneity for ACTN4 alterations was documented in carcinomatous components; the better differentiated carcinoma components exhibited fewer alterations than those with poorly differentiated histology. Conclusion: Accumulative genomic gains of ACTN4, causing actinin-4 protein overexpression, drive the development and progression of ovarian CCAs with high-grade histology.

DOI： 10.1111/j.1365-2559.2011.04163.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1053/j.gastro.2011.11.041

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記述言語：英語   出版者・発行元：一般社団法人 日本生物物理学会  

DOI： 10.2142/biophys.52.S124_3

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記述言語：日本語   出版者・発行元：日本プロテオーム学会（日本ヒトプロテオーム機構）  

DOI： 10.14889/jhupo.2012.0.189.0

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記述言語：日本語   出版者・発行元：日本プロテオーム学会（日本ヒトプロテオーム機構）  

DOI： 10.14889/jhupo.2012.0.45.0

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DOI： 10.5402/2012/768190

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DOI： 10.1155/2012/897412

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

Background: The aim of this study was to identify a new plasma biomarker for use in early detection of colorectal cancer.
Methods: Using the combination of hollow fiber membrane (HFM)-based low-molecular weight protein enrichment and two-dimensional image converted analysis of liquid chromatography and mass spectrometry (2DICAL), we compared the plasma proteome of 22 colorectal cancer patients with those of 21 healthy controls. An identified biomarker candidate was then validated in two larger cohorts [validation-1 (n = 210) and validation-2 (n = 113)] using a high-density reverse-phase protein microarray.
Results: From a total of 53,009 mass peaks, we identified 103 with an area under curve (AUC) value of 0.80 or higher that could distinguish cancer patients from healthy controls. A peak that increased in colorectal cancer patients, with an AUC of 0.81 and P value of 0.0004 (Mann-Whitney U test), was identified as a product of the PLIN2 gene [also known as perilipin-2, adipose differentiation-related protein (ADRP), or adipophilin]. An increase in plasma adipophilin was consistently observed in colorectal cancer patients, including those with stage I or stage II disease (P &lt; 0.0001, Welch&apos;s t test). Immunohistochemical analysis revealed that adipophilin is expressed primarily in the basal sides of colorectal cancer cells forming polarized tubular structures, and that it is absent from adjacent normal intestinal mucosae.
Conclusions: Adipophilin is a plasma biomarker potentially useful for the detection of early-stage colorectal cancer.
Impact: The combination of HFM and 2DICAL enables the comprehensive analysis of plasma proteins and is ideal for use in all biomarker discovery studies. Cancer Epidemiol Biomarkers Prev; 20(10);2195-203. (C) 2011 AACR.

DOI： 10.1158/1055-9965.EPI-11-0400

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

Objective: Emerging molecular targeting therapeutics have been incorporated into the management of advanced renal cell carcinoma; however, their efficacy remains limited. The aim of this study was to catalog potential therapeutic target molecules for renal cell carcinoma.
Methods: We first selected genes up-regulated in clear cell renal cell carcinoma relative to surrounding normal kidney tissues in 10 patients (Study Cohort) using high-density exon arrays that detect all potential transcripts predicted in the human genome. The selected genes were subjected to independent validation in another set of 10 patients (Validation Cohort) using real-time reverse transcriptase polymerase chain reaction and functional screening using small interfering RNA in six clear cell renal cell carcinoma cell lines.
Results: We identified 164 genes whose expression was significantly elevated in clear cell renal cell carcinoma (P &lt; 0.0001 [Student's t-test] and at least a 3-fold change in transcription signal). We finally extracted 33 genes required for maintaining cell proliferation in at least two clear cell renal cell carcinoma cell lines. The 33 genes included 13 genes known to be associated with the development/progression of renal cell carcinoma, including CAIX and FLT-1, confirming the robustness of the current strategy.
Conclusions: Through a combination of genome-wide expression and functional assays, we identified a set of genes with high potential as targets for drug development. This method is rapid and comprehensive and could be applied to the discovery of diagnostic biomarkers and therapeutic targets for cancers other than clear cell renal cell carcinoma.

DOI： 10.1093/jjco/hyr060

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記述言語：日本語   出版者・発行元：日本脳腫瘍病理学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

The development of a new plasma biomarker for early detection would be necessary to improve the overall outcome of colorectal cancer. Here we report the identification and validation of the ninth component of complement (C9) as a novel plasma biomarker for colorectal cancer by cutting-edge proteomic technologies. Plasma proteins were enzymatically digested into a large array of peptides, and the relative quantity of a total of 94 803 peptide peaks was compared between 31 colorectal cancer patients and 59 age/sex-matched healthy controls using 2D image-converted analysis of liquid chromatography and mass spectrometry. The selected biomarker candidates were validated in 345 subjects (115 colorectal cancer patients and 230 age/sex-matched healthy controls) using high-density reverse-phase protein microarrays. Plasma levels of Apo AI and C9 in colorectal cancer patients significantly differed from healthy controls with P values of 7.94 x 10(-4) and 1.43 x 10(-12) (Student&apos;s t-test), respectively. In particular, C9 was elevated in patients with colorectal cancer, including those with stage-I and -II diseases (P = 3.01 x 10(-3) and P = 1.13 x 10(-5), respectively). Although the significance of the present study must be validated in an independent clinical study, the increment of plasma C9 may be applicable to the early detection of colorectal cancer. (Cancer Sci 2011; 102: 630-638)

DOI： 10.1111/j.1349-7006.2010.01818.x

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記述言語：日本語   出版者・発行元：(一社)日本病理学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

Background: Early detection is essential to improve the outcome of patients with pancreatic cancer. A noninvasive and cost-effective diagnostic test using plasma/serum biomarkers would facilitate the detection of pancreatic cancer at the early stage.
Methods: Using a novel combination of hollow fiber membrane-based low-molecular-weight protein enrichment and LC-MS-based quantitative shotgun proteomics, we compared the plasma proteome between 24 patients with pancreatic cancer and 21 healthy controls (training cohort). An identified biomarker candidate was then subjected to a large blinded independent validation (n = 237, validation cohort) using a high-density reverse-phase protein microarray.
Results: Among a total of 53,009 MS peaks, we identified a peptide derived from CXC chemokine ligand 7 (CXCL7) that was significantly reduced in pancreatic cancer patients, showing an area under curve (AUC) value of 0.84 and a P value of 0.00005 (Mann-Whitney U test). Reduction of the CXCL7 protein was consistently observed in pancreatic cancer patients including those with stage I and II disease in the validation cohort (P &lt; 0.0001). The plasma level of CXCL7 was independent from that of CA19-9 (Pearson&apos;s r = 0.289), and combination with CXCL7 significantly improved the AUC value of CA19-9 to 0.961 (P = 0.002).
Conclusions: We identified a significant decrease of the plasma CXCL7 level in patients with pancreatic cancer, and combination of CA19-9 with CXCL7 improved the discriminatory power of the former for pancreatic cancer.
Impact: The present findings may provide a new diagnostic option for pancreatic cancer and facilitate early detection of the disease. Cancer Epidemiol Biomarkers Prev; 20(1); 160-71. (C) 2011 AACR.

DOI： 10.1158/1055-9965.EPI-10-0397

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：IOS PRESS  

Background: Early detection would be one of the most effective means to improve the outcome of renal cell carcinoma (RCC). We searched for a new plasma marker for RCC using a label-free quantitative shotgun proteomics method.
Methods: Plasma proteins were digested by trypsin, and the resulting peptides were analyzed by 2-Dimensional Image Converted Analysis of Liquid chromatography mass spectrometry (2DICAL). An identified biomarker candidate was subjected to validation using the Amplified Luminescent Proximity Homogeneous Assay (AlphaLISA).
Results: Among a total of 23,407 independent MS peaks, we found that the mean intensity of 59 peaks significantly differed between 20 clear cell RCC patients and 20 healthy controls. MS/MS spectra from 16 of the 59 peaks matched the amino acid sequences of the fibronectin 1 (FN1) gene product. The increased plasma level of FN1 in RCC patients was validated in a cohort of in 77 patients and 130 healthy controls (p &lt; 0.0001).
Conclusions: The FN1 is considered to be a promising biomarker candidate for clear cell RCC. Furthermore, AlphaLISA is an alternate to the conventional enzyme-linked immunosorbent assay and should prove useful for the rapid validation of biomarker candidates.

DOI： 10.3233/CBM-2012-0243

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記述言語：日本語   出版者・発行元：日本プロテオーム学会（日本ヒトプロテオーム機構）  

DOI： 10.14889/jhupo.2011.0.69.0

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Wnt signaling pathways play important roles in various stages of developmental events and several aspects of adult homeostasis. Aberrant activation of Wnt signaling has also been associated with several types of cancer. We have recently identified Traf2- and Nck-interacting kinase (TNIK) as a novel activator of Wnt signaling through a comprehensive proteomic approach in human colorectal cancer cell lines. TNIK is an activating kinase for T-cell factor-4 (TCF4) and essential for the beta-catenin-TCF4 transactivation and colorectal cancer growth. Here, we report the essential role of TNIK in Wnt signaling during Xenopus development. We found that Xenopus TNIK (XTNIK) was expressed maternally and that the functional knockdown of XTNIK by catalytically inactive XTNIK (K54R) or antisense morpholino oligonucleotides resulted in significant malformations with a complete loss of head and axis structures. XTNIK enhanced beta-catenin-induced axis duplication and the expression of beta-catenin-TCF target genes, whereas knockdown of XTNIK inhibited it. XTNIK was recruited to the promoter region of beta-catenin-TCF target genes in a beta-catenin-dependent manner. These results demonstrate that XTNIK is an essential factor for the transcriptional activity of the beta-catenin-TCF complex and dorsal axis determination in Xenopus embryos.

DOI： 10.1074/jbc.M109.090597

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

T-cell factor-4 (TCF4) is a transcription factor essential for maintaining the undifferentiated status and self-renewal of intestinal epithelial cells. It has therefore been considered that constitutive activation of TCF4 by aberrant Wnt signaling is a major force driving colorectal carcinogenesis. We previously identified Traf2- and Nck-interacting kinase (TNIK) as one of the proteins that interact with TCF4 in colorectal cancer cells, but its functional significance has not been elucidated. Here, we report that TNIK is an activating kinase for TCF4 and essential for colorectal cancer growth. TNIK, but not its catalytically inactive mutant, phosphorylated the conserved serine 154 residue of TCF4. Small interfering RNA targeting TNIK inhibited the proliferation of colorectal cancer cells and the growth of tumors produced by injecting colorectal cancer cells s.c. into immunodeficient mice. The growth inhibition was abolished by restoring the catalytic domain of TNIK, thus confirming that its enzyme activity is essential for the maintenance of colorectal cancer growth. Several ATP-competing kinase inhibitors have been applied to cancer treatment and have shown significant activity. Our findings suggest TNIK as a feasible target for pharmacologic intervention to ablate aberrant Wnt signaling in colorectal cancer. Cancer Res; 70(12); 5024-33. (C)2010 AACR.

DOI： 10.1158/0008-5472.CAN-10-0306

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

Purpose: The outcome of patients with advanced hepatocellular carcinoma (HCC) has remained unsatisfactory. Patients with HCC suffer from chronic hepatitis or liver cirrhosis, and their reserve liver function is often limited.
Experimental Design: To develop new therapeutic agents that act specifically on HCC but interfere only minimally with residual liver function, we searched for genes that were upregulated in 20 cases of HCC [namely, discovery sets 1 (n = 10) and 2 (n = 10)] in comparison with corresponding nontumorous liver and a panel representing normal organs using high-density microarrays capable of detecting all exons in the human genome.
Results: Eleven transcripts whose expression was significantly increased in HCC were subjected to siRNA-based secondary screening of genes required for HCC cell proliferation as well as quantitative reverse transcription-PCR analysis [validation sets 1 (n = 20) and 2 (n = 44)] and immunohistochemistry (n = 19). We finally extracted four genes, AKR1B10, HCAP-G, RRM2, and TPX2, as candidate therapeutic targets for HCC. siRNA-mediated knockdown of these candidate genes inhibited the proliferation of HCC cells and the growth of HCC xenografts transplanted into immunodeficient mice.
Conclusions: The four genes we identified were highly expressed in HCC, and HCC cells are highly dependent on these genes for proliferation. Although many important genes must have been overlooked, the selected genes were biologically relevant. The combination of genome-wide expression and functional screening described here is a rapid and comprehensive approach that could be applied in the identification of therapeutic targets in any type of human malignancy. Clin Cancer Res; 16(9); 2518-28. (C) 2010 AACR.

DOI： 10.1158/1078-0432.CCR-09-2214

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Although gemcitabine monotherapy is the standard treatment for advanced pancreatic cancer, patient outcome varies significantly, and a considerable number do not benefit adequately. We therefore searched for new biomarkers predictive of overall patient survival. Using LC-MS, we compared the base-line plasma proteome between 29 representative patients with advanced pancreatic cancer who died within 100 days and 31 patients who survived for more than 400 days after receiving at least two cycles of the same gemcitabine monotherapy. Identified biomarker candidates were then challenged in a larger cohort of 304 patients treated with the same protocol using reverse-phase protein microarray. Among a total of 45,277 peptide peaks, we identified 637 peaks whose intensities differed significantly between the two groups (p &lt; 0.001, Welch&apos;s t test). Two MS peaks with the highest statistical significance (p = 2.6 x 10(-4) and p = 5.0 x 10(-4)) were revealed to be derived from alpha(1)-antitrypsin and alpha(1)-antichymotrypsin, respectively. The levels of alpha(1)-antitrypsin (p = 8.9 x 10(-8)) and alpha(1)-antichymotrypsin (p = 0.001) were significantly correlated with the overall survival of the 304 patients. We selected alpha(1)-antitrypsin (p = 0.0001), leukocyte count (p = 0.066), alkaline phosphatase (p = 8.3 x 10(-8)), and performance status (p = 0.003) using multivariate Cox regression analysis and constructed a scoring system (nomogram) that was able to identify a group of high risk patients having a short median survival time of 150 days (95% confidence interval, 123-187 days; p = 2.0 x 10(-15), log rank test). The accuracy of this model for prognostication was internally validated and showed good calibration and discrimination with a boot-strap-corrected concordance index of 0.672. In conclusion, an increased level of alpha(1)-antitrypsin is a biomarker that predicts short overall survival of patients with advanced pancreatic cancer receiving gemcitabine monotherapy. Although an external validation study will be necessary, the current model may be useful for identifying patients unsuitable for the standardized therapy. Molecular & Cellular Proteomics 9:695-704, 2010.

DOI： 10.1074/mcp.M900234-MCP200

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

Pulmonary metastasis is the most significant prognostic determinant for osteosarcoma, but methods for its prediction and treatment have not been established. Using oligonucleotide microarrays, we compared the global gene expression of biopsy samples between seven osteosarcoma patients who developed pulmonary metastasis within 4 years after neoadjuvant chemotherapy and curative resection, and 12 patients who did not relapse. We identified argininosuccinate synthetase (ASS) as a gene differentially expressed with the highest statistical significance (Welch's t test, P = 2.2 x 10(-5)). Immunohistochemical analysis of an independent cohort of 62 osteosarcoma cases confirmed that reduced expression of ASS protein was significantly correlated with the development of pulmonary metastasis after surgery (log-rank test, P &lt; 0.05). Cox regression analysis revealed that ASS was the sole significant predictive factor (P = 0.039; hazard ratio, 0.319; 95% confidence interval, 0.108-0.945). ASS is one of the enzymes required for the production of a nonessential amino acid, arginine. We showed that osteosarcoma cells lacking ASS expression were auxotrophic for arginine and underwent G(0)-G(1) arrest in arginine-free medium, suggesting that an arginine deprivation therapy could be effective in patients with osteosarcoma. Recently, phase I and II clinical trials in patients with melanoma and hepatocellular carcinoma have shown the safety and efficacy of plasma arginine depletion by stabilized arginine deiminase. Our data indicate that in patients with osteosarcoma, reduced expression of ASS is not only a novel predictive biomarker for the development of metastasis, but also a potential target for pharmacologic intervention. Mol Cancer Ther; 9(3); 535-44. (C) 2010 AACR.

DOI： 10.1158/1535-7163.MCT-09-0774

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC MICROBIOLOGY  

Neurite outgrowth is the first step in the processes of neuronal differentiation and regeneration and leads to synaptic polarization and plasticity. Rab13 small G protein shows an increased mRNA expression level during neuronal regeneration; it is therefore thought to be involved in this process. We previously identified JRAB (junctional Rab13-binding protein)/MICAL-L2 (molecules interacting with CasL-like 2) as a novel Rab13 effector protein. Here, we show that Rab13 regulates neurite outgrowth in the rat pheochromocytoma cell line PC12 through an interaction with JRAB/MICAL-L2. The expression of JRAB/MICAL-L2 alone inhibits neurite outgrowth, whereas coexpression of the dominant active form of Rab13 rescues this effect. We also demonstrate an intramolecular interaction between the N-terminal calponin-homology (CH) and LIM domains of JRAB/MICAL-L2 and the C-terminal coiled-coil domain. Finally, we show that the binding of Rab13 to JRAB/MICAL-L2 stimulates the interaction of JRAB/MICAL-L2 with actinin-4, an actin-binding protein, which localizes to the cell body and the tips of the neurites in PC12 cells. These results suggest that Rab13 and JRAB/MICAL-L2 may act to transfer actinin-4 from the cell body to the tips of neurites, where actinin-4 is involved in the reorganization of the actin cytoskeleton which results in neurite outgrowth.

DOI： 10.1128/MCB.01067-09

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Neurite outgrowth is the first step in the processes of neuronal differentiation and regeneration and leads to synaptic polarization and plasticity. Rab13 small G protein shows an increased mRNA expression level during neuronal regeneration; it is therefore thought to be involved in this process. We previously identified JRAB (junctional Rab13-binding protein)/MICAL-L2 (molecules interacting with CasL-like 2) as a novel Rab13 effector protein. Here, we show that Rab13 regulates neurite outgrowth in the rat pheochromocytoma cell line PC12 through an interaction with JRAB/MICAL-L2. The expression of JRAB/MICAL-L2 alone inhibits neurite outgrowth, whereas coexpression of the dominant active form of Rab13 rescues this effect. We also demonstrate an intramolecular interaction between the N-terminal calponin-homology (CH) and LIM domains of JRAB/MICAL-L2 and the C-terminal coiled-coil domain. Finally, we show that the binding of Rab13 to JRAB/MICAL-L2 stimulates the interaction of JRAB/MICAL-L2 with actinin-4, an actin-binding protein, which localizes to the cell body and the tips of the neurites in PC12 cells. These results suggest that Rab13 and JRAB/MICAL-L2 may act to transfer actinin-4 from the cell body to the tips of neurites, where actinin-4 is involved in the reorganization of the actin cytoskeleton which results in neurite outgrowth.

DOI： 10.1128/MCB.01067-09

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記述言語：日本語   出版者・発行元：日本プロテオーム学会（日本ヒトプロテオーム機構）  

DOI： 10.14889/jhupo.2010.0.128.1

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記述言語：日本語   出版者・発行元：日本プロテオーム学会（日本ヒトプロテオーム機構）  

DOI： 10.14889/jhupo.2010.0.111.1

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記述言語：日本語   出版者・発行元：日本プロテオーム学会（日本ヒトプロテオーム機構）  

DOI： 10.14889/jhupo.2010.0.67.2

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記述言語：日本語   出版者・発行元：日本プロテオーム学会（日本ヒトプロテオーム機構）  

DOI： 10.14889/jhupo.2010.0.78.2

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC  

Osteosarcoma (OS) is the most frequent primary malignant bone tumor of children and young adults. Although the introduction of combined neoadjuvant chemotherapy has markedly improved survival, the outcome of OS patients with distant metastasis and/or poor response to chemotherapy is still unsatisfactory. Therefore there is a need to develop new therapeutic agents that suppress OS cell proliferation with higher efficacy. The protein kinases are a family of genes that play critical roles in various signaling pathways. Some cancer cells show addiction to constitutive activation of certain signaling pathways for proliferation and survival. To identify new drug targets for OS, we screened a panel of small interfering RNAs (siRNAs) that target 691 genes encoding human protein kinases and related proteins. We found that different constructs of siRNA specifically targeting polo-like 1 kinase (PLK1) significantly caused mitotic cell cycle arrest and subsequent apoptotic cell death in a variety of OS cell lines. siRNA targeting PLK1 also suppressed the growth of OS xenografts established in immunodeficient mice. Recently, phase I clinical trials of PLK1 chemical inhibitors have been reported. Our results indicate that PLK1 is a promising molecular target for pharmacologic intervention in OS. (Cancer Sci 2009; 100: 2268-2274).

DOI： 10.1111/j.1349-7006.2009.01310.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Plasma proteome analysis requires sufficient power to compare numerous samples and detect changes in protein modification, because the protein content of human samples varies significantly among individuals, and many plasma proteins undergo changes in the bloodstream. A label-free proteomics platform developed in our laboratory, termed "Two-Dimensional Image Converted Analysis of Liquid chromatography and mass spectrometry (2DICAL)," is capable of these tasks. Here, we describe successful detection of novel prolyl hydroxylation of alpha-fibrinogen using 2DICAL, based on comparison of plasma samples of 38 pancreatic cancer patients and 39 healthy subjects. Using a newly generated monoclonal antibody 11A5, we confirmed the increase in prolyl-hydroxylated alpha-fibrinogen plasma levels and identified prolyl 4-hydroxylase A1 as a key enzyme for the modification. Competitive enzyme-linked immunosorbent assay of 685 blood samples revealed dynamic changes in prolyl-hydroxylated alpha-fibrinogen plasma level depending on clinical status. Prolyl-hydroxylated alpha-fibrinogen is presumably controlled by multiple biological mechanisms, which remain to be clarified in future studies.

DOI： 10.1074/jbc.M109.041749

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC  

Clinical proteomics using a large archive of formalin-fixed paraffin-embedded (FFPE) tissue blocks has long been a challenge. Recently, a method for extracting proteins from FFPE tissue in the form of tryptic peptides was developed. Here we report the application of a highly sensitive mass spectrometry (MS)-based quantitative proteome method to a small amount of samples obtained by laser microdissection from FFPE tissues. Cancerous and adjacent normal epithelia were microdissected from FFPE tissue blocks of 10 squamous cell carcinomas of the tongue. Proteins were extracted in the form of tryptic peptides and analyzed by 2-dimensional image-converted analysis of liquid chromatography and mass spectrometry (2DICAL), a label-free quantitative proteomics method developed in our laboratory. From a total of 25 018 peaks we selected 72 mass peaks whose expression differed significantly between cancer and normal tissues (P &lt; 0.001, paired t-test). The expression of transglutaminase 3 (TGM3) was significantly down-regulated in cancer and correlated with loss of histological differentiation. Hypermethylation of TGM3 gene CpG islands was observed in 12 oral squamous cell carcinoma (OSCC) cell lines with reduced TGM3 expression. These results suggest that epigenetic silencing of TGM3 plays certain roles in the process of oral carcinogenesis. The method for quantitative proteomic analysis of FFPE tissue described here offers new opportunities to identify disease-specific biomarkers and therapeutic targets using widely available archival samples with corresponding detailed pathological and clinical records. (Cancer Sci 2009; 100: 1605-1611).

DOI： 10.1111/j.1349-7006.2009.01227.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC CLINICAL ONCOLOGY  

Purpose
Gemcitabine monotherapy is the current standard for patients with advanced pancreatic cancer, but the occurrence of severe neutropenia and thrombocytopenia can sometimes be life threatening. This study aimed to discover a new diagnostic method for predicting the hematologic toxicities of gemcitabine.
Patients and Methods
Using quantitative mass spectrometry (MS), we compared the baseline plasma proteomes of 25 patients who had developed severe hematologic adverse events (grade 3 to 4 neutropenia and/or grade 2 to 4 thrombocytopenia) within the first two cycles of gemcitabine with those of 22 patients who had not (grade 0).
Results
We identified 757 peptide peaks whose intensities were significantly different (P &lt; .001, Welch t test) among a total of 60,888. The MS peak with the highest statistical significance (P = .0000282) was revealed to be derived from haptoglobin by tandem MS. A scoring system (nomogram) based on the values of haptoglobin, haptoglobin phenotype, neutrophil count, platelet count, and body-surface area was constructed to estimate the risk of hematologic adverse events (grade 3 to 4 neutropenia and/or grade 2 to 4 thrombocytopenia) with an area under curve value of 0.782 in a cohort of 166 patients with pancreatic cancer. Predictive ability of the system was confirmed in two independent validation cohorts consisting of 87 and 52 patients with area under the curve values of 0.655 and 0.747, respectively.
Conclusion
Although the precise mechanism responsible for the correlation of haptoglobin with the future onset of hematologic toxicities remains to be clarified, our prediction model seems to have high practical utility for tailoring the treatment of patients receiving gemcitabine.

DOI： 10.1200/JCO.2008.19.9745

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Actinin-4, an isoform of non-muscular alpha-actinin, enhances cell motility by bundling the actin cytoskeleton. We previously reported a prognostic implication of high immunohistochemical expression of actinin-4 protein in ovarian cancers. Chromosomal gain or amplification of the 19q12-q13 region has been reported in ovarian cancer. We hypothesized that the actinin-4 (ACTN4) gene might be a target of the 19q12-q13 amplicon and play an essential role of ovarian cancer progression. In total, 136 advanced-stage ovarian cancers were investigated for the copy number of the ACTN4 gene on chromosome 19q13, using fluorescence in situ hybridization, and the correlation of the ACTN4 copy number with actinin-4 protein immunoreactivity and major clinicopathological factors was investigated. A higher copy number (&gt;= 4 copies) of the ACTN4 gene was detected in 29 (21%) cases and was highly associated with the intensity of actinin-4 immunoreactivity (P &lt; 0.0001), a high histological tumor grade (P=0.030), a clear-cell adenocarcinoma histology (P=0.012), resistance to first-line chemotherapies (P=0.028), and poor patient outcome (P=0.0011). Univariate analyses using the Cox regression model showed that a higher ACTN4 gene copy number was able to predict patient outcome more accurately than high actinin-4 immunoreactivity (relative risk: 2.48 vs 1.55). Multivariate analysis showed that a higher copy number of the ACTN4 gene and the degree of residual disease were independent prognostic factors for overall patient survival. The actinin-4 gene may be a target of the 19q amplicon, acting as a candidate oncogene, and serve as a predictor of poor outcome and tumor chemoresistance in patients with advanced-stage ovarian cancers.

DOI： 10.1038/modpathol.2008.234

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC  

We previously reported the development of an integrated proteome platform, namely 2-Dimensional Image Converted Analysis of Liquid chromatography and mass spectrometry (2DICAL), for quantitative comparison of large peptide datasets generated by nano-flow liquid chromatography (LC) and mass spectrometry (MS). The key technology of 2DICAL was the precise adjustment of the retention time of LC by dynamic programming. In order to apply 2DICAL to clinical studies that require comparison of a large number of patient samples we further refined the calculation algorithm and increased the accuracy and speed of the peptide peak alignment using a greedy algorithm, which had been used for fast DNA sequence alignment. The peptide peaks of each sample with the same m/z were extracted every 1 m/z and displayed with along the horizontal axis. Here we report a precise comparison of more than 150 000 typtic peptide ion peaks derived from 70 serum samples (40 patients with uterine endometrial cancer and 30 controls). The levels of 49 MS peaks were found to differ significantly between cancer patients and controls (P &lt; 0.01, Welch&apos;s t-test and interquartile range [IQR] of &gt; 40), and the differential expression and identification of selected three proteins was validated by immunoblotting. 2DICAL was is highly advantageous for large-scale clinical proteomics because of its simple procedure, high throughput, and quantification accuracy. (Cancer Sci 2009; 100: 514-519).

DOI： 10.1111/j.1349-7006.2008.01055.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC CLINICAL ONCOLOGY  

Purpose The majority of gastrointestinal stromal tumors (GIST) can be cured by surgery alone, but relapse occurs in 20% to 40% of cases. GISTs are considered to invariably arise through gain of function KIT or PDGFA mutation of the interstitial cells of Cajal (ICC). However, the genetic basis of the malignant progression of GISTs are poorly understood.
Patients and Methods The expression levels of 54,613 probe sets in 32 surgical samples of untreated GISTs of the stomach and small intestine were analyzed with oligonucleotide microarrays. The representative GeneChip data were validated by real-time reverse transcriptase polymerase chain reaction and immunohistochemistry.
Results Unbiased hierarchical clustering consistently separated the 32 cases of GIST into two major classes according to tumor site. The two major classes were further separated into novel subclasses, which were significantly correlated with various pathological prognostic parameters, the frequency of metastasis (P &lt;.05), and clinical outcome. Immunohistochemical analysis of 152 independent patients with gastric GISTs revealed that the expression of dipeptidyl peptidase IV (T-cell activation antigen CD26) protein was significantly associated with poorer overall and disease-free survival (P &lt;.00001).
Conclusion CD26 appears to be a reliable biomarker of malignant GISTs of the stomach. The postoperative recurrence rate of CD26-negative cases was as low as 2.0% (two of 102). Therefore, postoperative follow-up of such patients might be made less intensive. CD26 may play an important role in the malignant progression of gastric GISTs and serve as a therapeutic target.

DOI： 10.1200/JCO.2007.14.2331

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

Purpose: An invasive growth pattern is one of the hallmarks of pancreatic ductal carcinoma. Actinin-4 is an actin-binding protein associated with enhanced cell motility, invasive growth, and lymph node metastasis. Actinin-4 might play an important role in the development and progression of pancreatic cancer.
Experimental Design: The expression of actinin-4 was examined immunohistochemically in 173 cases of invasive pancreatic ductal carcinoma. The copy number of the actinin-4 (ACTN4) gene was calculated by fluorescence in situ hybridization. The expression of actinin-4 was stably knocked down by short hairpin RNA, and tumorigenicity was evaluated by orthotopic implantation into mice with severe combined immunodeficiency.
Results: The expression level of actinin-4 was increased in 109 (63.0%) of 173 cases of pancreatic cancer. Kaplan-Meier survival curves revealed that patients with increased expression of actinin-4 had a significantly poorer outcome (P = 0.00001, log-rank test). Multivariate analysis by the Cox proportional hazard model showed that high expression of actinin-4 was the most significant independent negative predictor of survival (hazard ratio, 2.33; P = 0.000009). Amplification (defined as more than four copies per interphase nucleus) of the ACTN4 gene was detected in 11 (37.9%) of 29 cases showing increased expression of actinin-4. Knockdown of actinin-4 expression inhibited the destructive growth of cancer cells in the pancreatic parenchyma.
Conclusion: Recurrent amplification of chromosome 19q13.1-2 has been reported in pancreatic cancer, but the exact target gene has not been identified. Actinin-4 contributes to the invasive growth of pancreatic ductal carcinoma, and ACTN4 is one of the candidate oncogenes in this chromosome locus.

DOI： 10.1158/1078-0432.CCR-08-0075

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：W B SAUNDERS CO-ELSEVIER INC  

Background & Aim: The function of beta-catenin as a transcriptional coactivator of T-cell factor-4 (TCF-4) is crucial for colorectal carcinogenesis. However, beta-catenin has no nuclear localization signal, and the mechanisms by which beta-catenin is imported into the nucleus and forms a complex with the TCF-4 nuclear protein are poorly understood. Methods: Proteins of 2 colorectal cancer cell lines, HCT-116 and DLD1, were immunoprecipitated with anti-TCF-4 antibody and analyzed directly by nanoflow liquid chromatography and mass spectrometry. The functional significance of nuclear pore complex (NPC) proteins in Wnt signaling was evaluated by in vitro and in vivo sumoylation, luciferase reporter, and colony formation assays. Results: TCF-4 interacted with a large variety of NPC proteins including ras-related nuclear protein (Ran), Ran binding protein-2 (RanBP2), and Ran GTPase-activating protein-1 (RanGAP1). The NPC protein RanBP2 functioned as the small ubiquitin-related modifier (SUMO) E3 ligase of TCF-4, and sumoylation of TCF-4 enhanced the interaction between TCF-4 and P-catenin. The overexpression of NPC proteins increased the nuclear import of the TCF-4 and beta-catenin proteins and enhanced the transcriptional activity. NPC proteins increased the growth of colorectal cancer cells, whereas sentrin-specific protease-2 inhibited it. Conclusions: Through a comprehensive proteomics approach, we revealed that NPC functions as a novel regulator of Wnt signaling and is possibly involved in colorectal carcinogenesis. A new drug targeting the interactions of TCF-4 with NPC proteins as well as their sumoylation activity might be effective for suppressing aberrant Wnt signaling and the proliferation of colorectal cancer cells.

DOI： 10.1053/j.gastro.2008.03.010

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Actinin-4 is an isoform of non-muscular alpha-actinin and actin-bundling protein. By enhancing cell motility, actinin-4 shows different biological properties from another isoform of non-muscular actinin 'actinin-1' and variable clinicopathological implications of actinin-4 have been demonstrated in some human malignancies such as breast cancers, lung cancers, and colorectal cancers. We herein described the clinicopathological and prognostic significance of actinin-4 expression in ovarian cancers. Actinin-4 expression was analyzed immunohistochemically in 265 primary ovarian carcinomas: 116 serous, 71 clear cell, 43 endometrioid, and 35 mucinous adenocarcinomas. With reference to endothelial immunoreactivity, cytoplasmic expression of actinin-4 was classified as either low ( including negative) or high. Then, various parameters such as patients' characteristics, histopathological findings including E-cadherin and beta-catenin immunoreactivity, and clinical outcome, were compared between groups showing differences in the intensity or intracellular distribution of actinin-4 immunoreactivity. High expression of actinin-4 was demonstrated in 137 (57%) cases and was associated with serous histology ( P=0.0075), high histological grade ( P &lt; 0.0001), an advanced disease stage (P=0.036), a high degree of residual disease after initial surgery (P=0.0047), poor patient outcome (5-year survival: 52.4% in the high-expression group vs 71.9% in the low expression group, P=0.0043 by log-rank test), and also with reduced E-cadherin and preserved beta-catenin expressions (P=0.0097 and 0.017, respectively). Nuclear immunoreactivity for actinin-4 was detected in 20 (7.5%) cases and was associated with low histological grade (P=0.0079) but not with other variables. Multivariate analysis showed that high actinin-4 expression was an independent prognostic factor for overall survival, as well as a high degree of residual disease and clear-cell histology. Accumulation of actinin-4 in the cytoplasm may be related to a higher propensity for tumor invasiveness and metastasis, probably by enhancing cell motility, and could be a novel prognostic indicator for patients with ovarian carcinomas.

DOI： 10.1038/modpathol.3800966

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING  

Aberrant transactivation of a certain set of target genes by the beta-catenin and T-cell factor-4 nuclear complex has been considered crucial for the initiation of colorectal carcinogenesis. We previously identified splicing factor-1 (SF1) as a novel component of the beta-catenin and T-cell factor-4 complex, and showed that the overexpression of SF1 inhibited the gene transactivational activity of the complex and markedly suppressed beta-catenin-evoked colony formation by human embryonic kidney 293 cells. However, the involvement of SF1 in the process of carcinogenesis in vivo remains unclear. In the present study, we established SF1-knockout mice using the gene trapping method. Homozygous mice (Sf1(-/-)) died during embryonic development before embryonic day (E)8.5, whereas heterozygous (Sf1(+/-)) mice were born alive and developed normally. Azoxymethane (AOM) was given at a dose of 10 mg/kg body weight once a week for 6 weeks to 7-week-old Sf1(+/-) and Sf1(+/+) mice. At 23 weeks after the start of AOM the average number (5.5 +/- 0.6 versus 2.2 +/- 0.2 in females [P = 0.003, Mann-Whitney U-test], 3.7 +/- 0.2 versus 1.7 +/- 0.7 in males [P = 0.014]) and volume of colon tumors per mouse (8.7 +/- 1.6 versus 2.2 +/- 0.5 mm(3) per female [P = 0.0008], 11.3 +/- 3.4 versus 0.6 +/- 0.2 mm(3) per male [P = 0.001]) were significantly higher in Sf1(+/-) than in Sf1(+/+) mice. The increased susceptibility of Sf1(+/-) mice to AOM-induced colon tumorigenesis indicates the crucial involvement of SF1 in the beta-catenin-mediated regulation of proliferation and differentiation of intestinal epithelial cells.

DOI： 10.1111/j.1349-7006.2007.00629.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：W B SAUNDERS CO-ELSEVIER INC  

Background & Aims: The Wnt signaling pathway is activated constitutively in the majority of colorectal cancers as a result of mutation in either the adenomatous polyposis coli or the CTNNB1 gene, and blockage of the pathway has been considered feasible as molecular therapy against colorectal cancer. DNA topoisomerase II alpha (Topo II alpha) is a component of the beta-catenin/ T-cell factor-4 (TCF-4) nuclear complex. We examined the functional significance of Topo IIa in Writ signaling. Methods: The physical and functional interaction between Topo II alpha and the beta-catenin/TCF-4 nuclear complex was evaluated by immunoprecipitation, immunofluorescence microscopy, 2-hybrid assay, and luciferase reporter assay. Results: Amino acids 9511301 of Topo II alpha were necessary for binding to beta-catenin. Over expression of Topo II alpha enhanced the TCF/lymphoid enhancer factor transcriptional activity in a dose-dependent manner, and knockdown of Topo II alpha by RNA interference conversely attenuated the transcriptional activity. The Topo II inhibitors, merbarone and etoposide, suppressed the beta-catenin-mediated TCF/lymphoid enhancer factor transcriptional activity. The catalytic activity of Topo II was augmented by overexpression of beta-catenin as measured by the decatenation of kinetoplast DNA. Topo II alpha was highly expressed and colocalized with beta-catenin in tumor cells of patients with familial adenomuatous polyposis syndrome and patients with sporadic colorectal cancer. Conclusions: Topo II alpha interacts with beta-catenin as a novel transcriptional co-activator. A new drug targeting the interaction of Topo II alpha with (beta-catenin as well as its catalytic activity might be more effective for suppressing aberrant Wnt signaling and proliferation of colorectal cancer cells than the current Topo II inhibitors.

DOI： 10.1053/j.gastro.2007.08.011

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PROFESSOR D A SPANDIDOS  

We examined whether serum protein profiling is a reliable index for prediction of therapeutic efficacy of preoperative chemoradiotherapy (PCRT) in advanced esophageal cancer compared with evaluation of the efficacy of conventional clinical examination. We entered 42 patients who received PCRT and surgery between 1998 and 2002 into this study. Serum protein profiling was performed using the preoperative serum of the patient to select the marker set that enabled the efficacy of PCRT to be evaluated accurately. The efficacy of PCRT was predicted with the marker set, and the sensitivity, specificity and accuracy of the method were calculated based on evaluation of the efficacy by pathological examination. Similarly, therapeutic efficacy was also predicted based on evaluation of the efficacy of conventional clinical examination, and the results were compared with those of prediction by serum protein profiling. The correlation between each predictive examination and outcome was evaluated. The sensitivity, specificity and accuracy of prediction of therapeutic efficacy of PCRT by serum protein profiling were 90.9, 100 and 93.3%, respectively. In clinical examination, prediction of the efficacy of PCRT by three methods was as follows: by esophagography, sensitivity 76.0%, specificity 17.6%, accuracy 52.4%; by endoscopy, sensitivity 80.0%, specificity 11.8%, accuracy 52.4%; by computed tomography, sensitivity 60.0%, specificity 47.1%, accuracy 54.8%, respectively. These results demonstrated the superiority of serum protein profiling in predicting the therapeutic efficacy of PCRT compared with conventional clinical examination. Moreover, serum protein profiling was the only significant prognostic factor as regards the correlation with outcome by multivariate analysis.

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記述言語：日本語   出版者・発行元：JAPANESE BIOCHEMICAL SOC  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

We investigated the aberrant expression of plasma proteins in patients with pancreatic cancer. High-abundance plasma proteins (albumin, transferrin, haptoglobin, alpha-1-antitrypsin, IgG and IgA) were depleted by use of an immuno-affinity column, and low-abundance ones were separated into five fractions by anion-exchange chromatography. The fractionated plasma proteins were subjected to 2D-DIGE with highly sensitive fluorescent dyes. The quantitative protein expression profiles obtained by 2D-DIGE were compared between two plasma protein mixtures: one from five non-cancer bearing healthy donors and the other from five patients with pancreatic cancer. Among 1200 protein spots, we found that 33 protein spots were differently expressed between the two mixtures; 27 of these were up-regulated and six were down-regulated in cancer. Mass spectrometry and database searching allowed the identification of the proteins corresponding to the gel spots. Up-regulation of leucine-rich alpha-2-glycoprotein (LRG), which has not previously been implicated in pancreatic cancer, was observed. Western blotting with an anti-LRG antibody validated the up-regulation of LRG in an independent series of plasma samples from healthy controls, patients with chronic pancreatitis, and patients with pancreatic cancer. Our results demonstrate the application of a combination of multi-dimensional liquid chromatography with 2D-DIGE for plasma proteomics and suggest the clinical utility of LRG plasma level measurement. (C) 2007 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jchromb.2007.01.029

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING  

The incidence of endometrial cancer is predicted to increase in developed countries. Because of the relatively high incidence of complications and low diagnostic sensitivity associated with endometrial tissue sampling, there is an urgent need for the development of a safe and non-invasive diagnostic method. The proteomic spectrum of albumin-associated peptides was obtained from a total of 125 serum samples (92 from endometrial cancer patients and 33 from controls) by matrix-assisted laser desorption/ionization hybrid quadrupole time-of-flight mass spectrometry, and the candidate markers were selected by the Mann-Whitney U-test and receiver operator characteristics analysis. We selected three mass peaks at 4769, 6254 and 11 792 m/z from a total of 507 peaks as distinguishing cancer patients from controls (P &lt; 0.00001 and area under curve of over 0.8). When the cut-off points were defined as the averages of the values in the controls + 2 SD, the combination of the three peptides detected endometrial cancer with a sensitivity of 65.2% (60/92). Even stage I early endometrial cancers were detected with a sensitivity of 60.3% (38/63). Unfortunately, the three peptides were also detected in 44.6% (33/74) of myoma uteri patients, indicating that they are not specific to endometrial cancer. Although a large-scale study is necessary to confirm the clinical significance of the peptide biomarkers identified in this study, direct profiling of serum-albumin-bound peptides by high-resolution mass spectrometry was proven to have potential as a means of identifying biomarkers for a variety of diseases.

DOI： 10.1111/j.1349-7006.2007.00458.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Actinin-4 was originally identified as an actin-binding protein associated with cell motility and cancer invasion and metastasis. However, actinin-4 forms complexes with a large number of different partner proteins and is speculated to have several distinct functions depending on its partner. The level of actinin-4 expression was found to be significantly lower in prostate cancer cells than in non-cancerous basal cells, and restoration of actinin-4 expression inhibited cell proliferation by prostate cancer cell line 22RV1. Immunoprecipitation and mass spectrometry analysis revealed that actinin-4 forms native complexes with several partner proteins in 22RV1 cells, including with beta/gamma-actin, calmodulin, the clathrin heavy chain, non-muscular myosin heavy chain, heterogeneous nuclear ribonucleoprotein All, and Ras-GTPase-activating protein SH3 domain-binding protein. Clathrin is a coat protein that covers the internalized membrane pit that forms during early endocytosis. We found that other clathrin-related and unrelated cargo proteins, including dynamin, adaptin-delta, beta subunit of neuronal adaptin-like protein, and p47A, also interact with actinin-4. Immunofluorescence microscopy revealed that dynamin and clathrin co-localized with actinin-4 at the sites of membrane ruffling, and transfection of actinin-4 cDNA facilitated the transport of transferrin into perinuclear endosomes. Endocytosis terminates signaling evoked by cell surface receptors and regulates the recycling of receptors and ligands. We identified a panel of proteins whose expression and/or subcellular localization was regulated by actinin-4 by performing organelle fractionation and ICAT-LC-MS/MS. The decreased expression of actinin-4 protein in prostate cancer cells may cause aberrations in the intracellular trafficking of various cell surface molecules and contribute to carcinogenesis.

DOI： 10.1074/mcp.M600129-MCP200

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：W B SAUNDERS CO-ELSEVIER INC  

Background & Aims: beta-Catenin is the downstream effector of the Wnt signaling pathway and is involved in the process of colorectal carcinogenesis. However, it is still uncertain whether P-catenin exerts its oncogenic function solely by coactivating the target genes of T-cell factor-4 (TCF4). We previously reported that the beta-catenin/TCF4 complex contains several classes of RNA-binding proteins and regulates the premessenger RNA splicing reaction, but the identity of the exact effector molecule downstream of the beta-catenin/TCF4 complex has not been established. Methods: Using isotope-coded affinity tagging and mass spectrometry, we examined more than 4000 peptides derived from colorectal cancer cells and identified that splicing factor-1 (SF1) was one of the proteins whose expression is regulated by the beta-catenin/TCF4 complex. Results: The expression of SF1 was found to be correlated with the differentiation status of intestinal epithelial cells and inversely correlated with tumorigenesis. Immunoprecipitation and immunofluorescence microscopy revealed that SF1 was a complex, and beta-catenin-evoked gene transactivation and cell proliferation were negatively regulated by SF1 complementary DNA transfection. SF1 was essential for the induction of alternative splicing by the beta-catenin/TCF4 complex, and SF1 complementary DNA transfection induced known cancer-related splice variants, such as Wnt-induced secreted protein-1v and fibroblast growth factor receptor-3-ATII. Conclusions: The beta-catenin/TCF4 complex regulates the level of SF1 protein expression, and, conversely, SF1 interacts with the complex and regulates its gene transactivation and premessenger RNA splicing activities. Identification of the interaction may shed light on a novel aspect of the Writ signaling pathway.

DOI： 10.1053/j.gastro.2007.01.007

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

Formation of the T-cell factor-4 (TCF-4) and beta-catenin nuclear complex is considered crucial to embryonic development and colorectal carcinogenesis. We previously reported that poly(ADP-ribose) polymerase-1 (PARP-1) interacts with the TCF-4 and beta-catenin complex and enhances its transcriptional activity. However, its biological significance remains unexplained. Using immunoprecipitation and mass spectrometry, we found that two Ku proteins, Ku70 and Ku80, were also associated with the complex. Knockdown of Ku70 by RNA interference increased the amount of beta-catenin associated with TCF-4 and enhanced the transcriptional activity. PARP-1 competed with Ku70 for binding to TCF-4. Treatment with bleomycin, a DNA-damaging alkylating agent, induced polyADP-ribosylation of PARP-1 protein and inhibited its interaction with TCF-4. Bleomycin conversely increased the amounts of Ku70 coimmunoprecipitated with TCF-4 and removed beta-catenin from TCF-4. We propose a working model in which the transcriptional activity of TCF-4 is regulated by the relative amount of Ku70, PARP-1, and beta-catenin proteins binding to TCF-4. Identification of the functional interaction of Ku70 as well as PARP-1 with the TCF-4 and beta-catenin transcriptional complex may provide insights into a novel linkage between DNA damage recognition/repair and Wnt signaling.

DOI： 10.1158/0008-5472.CAN-06-2360

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

We developed an integrated platform consisting of machinery and software modules that can apply vast amounts of data generated by nanoflow LC-MS to differential protein expression analyses. Unlabeled protein samples were completely digested with modified trypsin and separated by low speed (200 nl/min) one-dimensional HPLC. Mass spectra were obtained every 1 s by using the survey mode of a hybrid Q-TOF mass spectrometer and displayed in a two-dimensional plane with m/z values along the x axis, and retention time was displayed along the y axis. The time jitter of nano-LC was adjusted using newly developed software based on a dynamic programming algorithm. The comprehensiveness (60,000-160,000 peaks above the predetermined threshold detectable in 60-mu g cell protein samples), reproducibility (average coefficient of variance of 0.35-0.39 and correlation coefficient of over 0.92 between duplicates), and accurate quantification with a wide dynamic range (over 103) of our platform warrant its application to various types of experimental and translational proteomics.

DOI： 10.1074/mcp.T500039-MCP200

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

The survival rate of pancreatic cancer patients is the lowest among those with common solid tumors, and early detection is one of the most feasible means of improving outcomes. We compared plasma proteomes between pancreatic cancer patients and sex- and age-matched healthy controls using surface- enhanced laser desorption/ionization coupled with hybrid quadrupole time-of-flight mass spectrometry. Proteomic spectra were generated from a total of 245 plasma samples obtained from two institutes. A discriminating proteomic pattern was extracted from a training cohort (71 pancreatic cancer patients and 71 healthy controls) using a support vector machine learning algorithm and was applied to two validation cohorts. We recognized a set of four mass peaks at 8,766, 17,272, 28,080, and 14,779 m/z, whose mean intensities differed significantly (Mann-Whitney U test, P &lt; 0.01), as most accurately discriminating cancer patients from healthy controls in the training cohort [sensitivity of 97.2% (69 of 71), specificity of 94.4% (67 of 71), and area under the curve value of 0.978]. This set discriminated cancer patients in the first validation cohort with a sensitivity of 90.9% (30 of 33) and a specificity of 91.1% (41 of 45), and its discriminating capacity was further validated in an independent cohort at a second institution. When combined with CA19-9, 100% (29 of 29 patients) of pancreatic cancers, including early-stage (stages I and 11) tumors, were detected. Although a multi-institutional large-scale study will be necessary to confirm clinical significance, the biomarker set identified in this study may be applicable to using plasma samples to diagnose pancreatic cancer.

DOI： 10.1158/0008-5472.CAN-05-1851

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

Purpose: Establishment of a reliable method of predicting the efficacy of chemotherapy and radiotherapy is necessary to provide the most suitable treatment for each cancer patient. We investigated whether proteomic profiles of serum samples obtained from untreated patients were capable of being used to predict the efficacy of combined preoperative chemoradiotherapy against esophageal cancer.
Experimental Design: Proteomic spectra were obtained from a training set of 27 serum samples (15 pathologically diagnosed responders to preoperative chemoradiotherapy and 12 non-responders) by surface-enhanced laser desorption and ionization coupled with hybrid quadrupole time-of-flight mass spectrometry. A proteomic pattern prediction model was constructed from the training set by machine learning algorithms, and it was then tested with an independent validation set consisting of serum samples from 15 esophageal cancer patients in a blinded manner.
Results: We selected a set of four mass peaks, at 7,420, 9,112,17,123, and 12,867 m/z, from a total of 859 protein peaks, as perfectly distinguishing responders from nonresponders in the training set with a support vector machine algorithm. This set of peaks (i.e., the classifier) correctly diagnosed chemoradiosensitivity in 93.3% (14 of 15) of the cases in the validation set.
Conclusions: Recent mass spectrometric approaches have revealed that serum contains a large volume of information that reflects the microenvironment of diseased organs. Although a multi-institutional large-scale study will be necessary to confirm each component of the classifier, there is a subtle but definite difference in serum proteomic profile between responders and nonresponders to chemoradiotherapy.

DOI： 10.1158/1078-0432.CCR-05-0656

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Purpose: Surface enhanced laser desorption/ionization mass spectrometry can generate robust information from a small amount of clinical samples such as serum and plasma. In this study we identified novel diagnostic biomarkers of renal cell carcinoma (RCC) by large-scale serum protein profiling using surface enhanced laser desorption/ionization mass spectrometry.
Materials and Methods: Proteomic spectra were generated by a time of flight mass spectrometer from a set of training samples (21 patients with RCC and 24 healthy volunteers) and another set of validation samples (19 patients with RCC, 20 healthy volunteers and 5 patients with pyelonephritis). Information on the peaks (intensity and m/z) was extracted from the mass spectra using newly developed algorithms, and the Mann-Whitney's U test and linear support vector machine were used to identify the peaks distinguishing RCC samples from the controls.
Results: Two peaks with molecular masses of 4,151 and 8,968 m/z were selected as significantly more prominent in RCC samples (p &lt;0.01) among the 3,539 peaks in the range of 3,000 to 30,000 m/z obtained from the training samples. Simultaneous recognition of these 2 biomarkers was shown to have a sensitivity of 89.5% for the diagnosis of RCC and an overall specificity of 80.0% (95% [19 of 20] of healthy volunteers and 20% [1 of 5] of patients with pyelonephritis) in the blinded validation samples, and to allow detection of RCC in stage I (UICC) in 88.9% (16 of 18) of the cases.
Conclusions: We identified 2 serum biomarkers potentially useful for the early diagnosis of RCC. This finding warrants a further large-scale multi-institutional analysis for clinical evaluation of the diagnostic significance of these biomarkers.

DOI： 10.1097/01.ju.0000173915.83164.87

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：W B SAUNDERS CO-ELSEVIER INC  

Background & Aims: beta-Catenin is a downstream effector of the Writ signaling pathway and is believed to exert its oncogenic function by activating T-cell factor (TCF)/lymphoid enhancer factor (LEF) family transcriptional factors. However, it is still uncertain whether the diverse effects of beta-catenin are caused solely by aberrant gene transactivation. In this study, we used a proteomics approach to obtain further insight into the functional properties of nuclear beta-catenin. Methods: The protein assembly of a native beta-catenin-containing complex in nuclear extracts from a colorectal cancer cell line, DLD-1, was identified using immunoprecipitation and mass spectrometry. Results : beta-Catenin physically interacted with fusion (FUS)/translocated in liposarcoma (TLS) and various RNA-binding proteins. The expression of FUS/TLS was closely associated with the accumulation of beta-catenin and with the undifferentiated status of intestinal epithelial cells. The transient transfection of FUS suppressed beta-catenin-evoked gene transactivation of TCF/LEF, and beta-catenin transfection affected the splicing pattern of the E1A minigene and induced a novel splicing variant of estrogen receptor (ER)-beta exerting a dominant-negative activity. Conclusions: Human cancer expresses a large variety of alternatively spliced messenger RNA (mRNA), but the precise molecular mechanisms responsible for cancer-related alternative splicing are largely unknown. In this study, we demonstrated the interaction of beta-catenin with FUS/TLS and other RNA-binding proteins involved in the regulation of pre-mRNA splicing. Certain mRNA splicing abbreviations seen in human cancers may be induced-by the activation of the Wnt signaling pathway.

DOI： 10.1053/j.gastro.2005.07.025

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

The E-cadherin/catenin system acts as an invasion suppressor of epithelial malignancies. This invasion suppressive activity seems be mediated not only by the cell adhesive activity of E-cadherin but by other undetermined signaling pathways elicited by beta-catenin. In fact, cancer cells that have infiltrated the stroma reduce the expression of E-cadherin and accumulate beta-catenin. We attempted to identify the alternative partner proteins that make complexes with catenin in the absence of E-cadherin. An similar to 100-kDa protein was constantly coimmunoprecipitated with beta-catenin from SW480 colorectal cancer cells, which lack the expression of E-cadherin, and was identified as actinin-4 by mass spectrometry. Transfection of E-cadherin cDNA suppressed the association between beta-catenin and actinin-4. Inhibition of E-cadherin by RNA interference transferred the beta-catenin and actinin-4 proteins into the membrane protrusions of DLD-1 cells. Immunofluorescence histochemistry of clinical colorectal cancer specimens showed that the beta-catenin and actinin-4 proteins were colocalized in colorectal cancer cells infiltrating the stroma. We reported previously that overexpression of actinin-4 induces cell motility and specifically promotes lymph node metastasis by colorectal cancer. The association between beta-catenin and actinin-4 and its regulation by E-cadherin may represent a novel molecular link connecting cell adhesion and motility. Shutting down the signals mediating this association may be worth considering as a therapeutic approach to cancer invasion and metastasis.

DOI： 10.1158/0008-5472.CAN-05-0718

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：W B SAUNDERS CO  

Background & Aims: T-cell factor (TCF)-4 regulates a certain set of genes related to growth and differentiation of intestinal epithelial cells. Aberrant transactivation of these TCF-4-regulated genes by beta-catenin protein plays a crucial role in early intestinal carcinogenesis, and the transcriptional machinery of the TCF-4/beta-catenin complex is likely to contain targets for molecular therapy. We explored the molecular composition of the TCF-4/beta-catenin transcriptional complex by means of proteomics. Methods & Results: A protein of approximately 112 kilodaltons was consistently coimmunoprecipitated with FLAG-tagged TCF-4 transiently expressed in HEK293 cells, and the protein was identified by mass spectrometry as poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 physically interacted with TCF-4 and augmented the transcriptional activity of the beta-catenin/TCF-4 complex. Knockdown of PARP-1 by RNA interference significantly suppressed both transcriptional activity and proliferation by colorectal cancer cells. Auto-polyADP-ribosylation of the PARP-1 protein induced by DNA damage inhibited the functional interaction of PARP-1 with TCF-4. PARP-1 was overexpressed in the intestinal adenomas of patients with familial adenomatous polyposis and multiple intestinal polyposis mice. The expression of PARP-1 was closely associated with the accumulation of beta-catenin and with the undifferentiated status of intestinal epithelial cells. Conclusions: In this study, we identified PARP-1 as a novel coactivator of the beta-catenin/TCF-4 complex. Although PARP-1 has been believed to play a protective role against carcinogenesis, these expression patterns and functional properties of PARP-1 were highly suggestive of its participation in early colorectal carcinogenesis.

DOI： 10.1053/j.gastro.2005.03.007

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Aberrant transactivation of a certain set of target genes by the beta-catenin and T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factor complexes has been implicated in the process of intestinal epithelial cells entering early colorectal carcinogenesis. A rat intestinal epithelial cell line IEC6 became elongated, extended protrusions at cell periphery, and increased stress fibers and focal contacts upon the induction of beta-catenin protein stabilized by deletion of the N-terminal glycogen synthase kinase-3 beta (GSK beta) phosphorylation sites (beta-catenin Delta N89). We used the GeneChip(TM) oligonucleotide microarray system to examine approximately 24 000 genes and identified 13 genes whose expression was altered during the course of this morphological transformation. Those genes included known negative regulators of the Wnt signaling pathway, Sfrp4 and Axin2; extracellular matrix and related molecule, Hxb and Crtl1; cell adhesion and cytoskeletal proteins, Podxl, Igaf4, and Itab6; and molecules involved in the insulin and insulin-like growth factor (IGF) signaling pathways, Enpp1, Igfbp2, and Sgk. We report the finding that insulin-like growth factor-binding protein-2 (IGFBP2) is a direct target gene of the beta-catenin and TCF/LEF complexes. The IGFBP2 protein interacts with integrins. Disruption of the multigene network system regulating cell adhesion and cytoskeleton may be crucial in the initiation of colorectal carcinogenesis.

DOI： 10.1038/sj.onc.1208517

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

Tissue factor (TF) is a transmembrane glycoprotein that plays roles in the blood coagulation and intracellular signaling pathways, and has also been suggested to modulate the biological behavior of cancer cells. In order to examine the clinicopathologic significance of TF expression in pancreatic ductal adenocarcinoma, TF expression was determined by immunohistochemistry using a newly raised anti-TF monoclonal antibody in 113 patients who had undergone surgical resection of pancreatic ductal adenocarcinoma. According to the incidence of tumor cell immunopositivity, patients were divided into "negative TF (0%), "weak TF (&lt;25%), or "high TF (25% or more) groups, which accounted for 11.6% (n = 13), 44.2% (n = 50), and 44.2% (n = 50) of the total, respectively. Increased TF expression was correlated with the extent of the primary tumor (P = 0.0043), lymph node metastasis (P = 0,0043), lymphatic distant metastasis (P 0.0039), advanced tumor-node-metastasis stage (P = 0.0002),and high tumor grade (P 0,0164). Multivariate analysis using the Cox proportional hazards model showed that high TF expression was an independent negative predictor for survival (hazard ratio, 2.014; P = 0.0076). Moreover, patients with TF-negative tumors had a significantly better prognosis even if lymph node metastasis was present (P &lt; 0.0001). We also showed that TF knockdown by RNA interference suppressed the invasiveness of a pancreatic adenocarcinoma cell line in vitro. These results indicate that TF expression may contribute to the aggressiveness of pancreatic ductal adenocarcinoma by stimulating tumor invasiveness, and that evaluation of the primary tumor for TF expression may identify patients with a poor prognosis.

DOI： 10.1158/1078-0432.CCR-04-0866

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：W B SAUNDERS CO  

Background &Aims: Enhanced motility of cancer cells by remodeling of the actin cytoskeleton seems crucial in the process of cancer invasion and metastasis. We previously identified an actin-binding protein, actinin-4, as a new biomarker of cancer invasion and an indicator of prognosis for patients with breast cancer. However, its involvement in the mechanisms of cancer invasion and metastasis remains undetermined. The current study tested the role of actinin-4 in the motility and metastatic potential of colorectal cancer cells.Methods & Results: Quantitative immunofluorescence histochemistry showed that the expression level of the actinin-4 protein was increased in 73.1% (19/26) of the cases of colorectal cancer over the corresponding normal intestinal epithelium. The increased expression of actinin-4 was most significant in dedifferentiated cancer cells at the invasive front. A colorectal cancer cell clone capable of inducing actinin-4 using the tetracycline-regulatory system (designated DLD1 Tetoff ACTN-4) was established. Upon the induction of actinin-4, DLD1 Tet-off ACTN-4 cells spread filopodia and significantly increased their motility (P =.00027); actinin-4 protein was concentrated at the leading edges of these actin-rich podia. When injected into the mesocecum of severe combined immunodeficient mice, DLD1 Tet-off ACTN4 cells, but not the control cells, metastasized into regional mesenteric lymph nodes, resembling the behavior of clinical cancers. The expression of actinin-4 in focally dedifferentiated cancer cells at the invasive front was significantly correlated with the frequency of lymph node metastasis of colorectal cancer (P =.038). Conclusions: Actinin-4 actively increases cell motility and promotes lymph node metastasis of colorectal cancer.

DOI： 10.1053/j.gastro.2004.10.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Tumor-associated alternative RNA splicing has gained considerable attention. We identified a novel alternative splice variant RNA of actinin-4 in human small cell lung caner (SCLC). Expression of the splice variant was highly specific to SCLC cell lines (10/10), biopsies (3/3), and testis. The variant encoded a peptide with a three amino-acid change in exon 8, where the germline missense mutation takes place in familial focal segmental glomerulosclerosis (FSGS). The variant protein showed high affinity to filamentous actin polymers and was not localized with cortical actin. Alternatively spliced actinin-4 may be a new diagnostic marker of SCLC and a candidate target for selective therapy.

DOI： 10.1038/sj.onc.1207652

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CHURCHILL LIVINGSTONE  

In this paper, we report one case of severe brain abscess in, which Porphyromonas gingivalis was detected in the spinal fluid. (C) 2004 The British Association of Oral. and Maxillofacial surgeons. Published by Elsevier Ltd. Alt rights reserved.

DOI： 10.1016/S0266-4356(03)00190-6

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PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CHURCHILL LIVINGSTONE  

Diagnosis of mucosa-associated lymphoid tissue (MALT) lymphoma based on histological examination alone is difficult. We report three patients with histologically suspected MALT lymphoma who developed lymphoprotiferative lesions of the sublingual gland. Seminested polymerase chain reaction (PCR) analysis applied to formalin-fixed and paraffin-embedded specimens showed clonal rearrangement of immunoglobulin heavy chain genes in two patients and a polyclonal characteristic in one. The clinical findings and Southern blot analysis confirmed the accuracy of the diagnosis. The molecular method. described can be applied routinely to processed specimens to obtain helpful information for the diagnosis of low-grade malignancies of lymphoproliferative disorders, such as MALT lymphoma. (C) 2003 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/S0266-4356(03)00233-X

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PubMed

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出版者・発行元：JAPANESE SOCIETY OF PEDIATRIC ORAL AND MAXILLOFACIAL SURGERY  

We described a 10-year-old female with a mucoepidermoid carcinoma arising in the palate. She had orthodontic treatment, then the doctor discovered a swelling in the right side of the palate in August, 1996. So the doctor removed orthodontic brace, but the swelling was unchanged. Therefore she visited our clinic. At first the lesion was thought to be a benign tumor. Because of a 26×21mm hemispherium pattern, there was painless swelling of the palate. A biopsy was performed, the tissue was thought to be a malignant tumor. With the patient under general anaesthesia, tumorectomy was performed. Pathological diagnosis was a mucoepidermoid carcinoma (moderate type). Later, extraction of 76_??_ and additional ectomy including alveolar bone were done.

DOI： 10.11265/poms1991.11.81

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記述言語：日本語   出版者・発行元：Japanese Society of Oral and Maxillofacial Surgeons  

We report the case of an HIV infected patient who was discovered during dental treatment. The patient was a 25-year-old man in whom oral candidiasis was diagnosed by a dentist. The clinical diagnosis was oral candidiasis with immunodeficiency. The patient had a history of sexual relations with many partners. Laboratory tests revealed markedly decreased CD4 (69.9/μl) and a CD 4/CD 8 ratio of 0.09. HIV antibody was positive on both particle agglutination (PA) and Western blot (WB) analysis.<BR>Since HIV infected patients show numerous oral manifestations, dentists and oral and maxillofacial surgeons have an important role in the diagnosis and treatment of AIDS.

DOI： 10.5794/jjoms.44.1002

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/1999111247

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMERICAN PHYSICAL SOC  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KYOTO UNIV  

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記述言語：日本語   出版者・発行元：日本医科大学医学会  

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J04260&link_issn=&doc_id=20211116290004&doc_link_id=%2Fcw1nimed%2F2021%2F001704%2F005%2F0146-0157%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcw1nimed%2F2021%2F001704%2F005%2F0146-0157%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(株)アークメディア  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：日本分子イメージング学会  

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記述言語：英語   出版者・発行元：(一社)日本耳鼻咽喉科頭頸部外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY  

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J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本口腔腫瘍学会  

後発転移を予防する目的に補助化学療法が実施されるが、そもそも原発巣が完全に切除されているのであれば、後発転移の有無は腫瘍が持つ個性である転移活性に依存する可能性が高い。すなわち、原発巣の腫瘍個性が分子生物学的にプロファイルできれば、最適な補助化学療法に対する戦略を提供できる可能性がある。われわれは、高転移性の乳がん、大腸がん、卵巣がん、膵がん、肺がん、唾液腺がん、舌がんで遺伝子増幅するアクチン束状化分子ACTN4の単離を行った。ACTN4タンパク質の高発現は、がん転移に関与する細胞突起の形成を誘導する。カナダで実施された非小細胞肺がんの補助化学療法に対するランダム化比較試験のトランスクリプトームのサブグループ解析では、ACTN4の高発現グループでのみで補助化学療法の上乗せ効果が確認できた。ACTN4の遺伝子増幅を検出するFISHプローブを開発し、I期肺腺がんの転移活性を予測し、適切な補助化学療法に資するバイオマーカーの臨床開発を開始した。遺伝子増幅により後発転移を予測できるのは、非小細胞肺がんだけではない。口腔がんについても後発転移ハイリスク集団を同定することで、適切な治療戦略を提示できる可能性はある。本バイオマーカーの臨床的意義について紹介する。(著者抄録)

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J02382&link_issn=&doc_id=20201221280002&doc_link_id=%2Fdy8ortum%2F2020%2F003204%2F003%2F0134-0143%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdy8ortum%2F2020%2F003204%2F003%2F0134-0143%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(一社)日本泌尿器科学会総会事務局  

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記述言語：日本語   出版者・発行元：日本医科大学医学会  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：日本語   出版者・発行元：日本分子イメージング学会  

J-GLOBAL

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J-GLOBAL

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：医薬ジャーナル社  

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2017029623

記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：OXFORD UNIV PRESS  

DOI： 10.1093/annonc/mdw392.39

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：OXFORD UNIV PRESS  

DOI： 10.1093/annonc/mdw381.6

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER SOC CLINICAL ONCOLOGY  

DOI： 10.1200/JCO.2016.34.15_suppl.4106

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記述言語：日本語   出版者・発行元：(一社)日本耳鼻咽喉科学会  

DOI： 10.3950/jibiinkoka.119.573

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER SOC CLINICAL ONCOLOGY  

DOI： 10.1200/jco.2016.34.4_suppl.759

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：(株)メディカルドゥ  

膵がんは,予後が不良な難治性のがんとして知られている。この疾患の発見には既存バイオマーカーであるCA19-9を用いているが,早期段階で検出はできず特異性も高くない。したがって,膵がんを早期に発見できる新規バイオマーカーを開発することが予後改善ひいては完治のために必要である。われわれは質量分析基盤プロテオミクスを用いて膵がんバイオマーカーapolipoprotein AII isoformを発見し,膵がんおよび膵がんリスク疾患バイオマーカーの開発を行った。現在,ELISA法を用いたキットを作成し,実用化に向けて発展させている。(著者抄録)

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：SPRINGER  

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記述言語：日本語   出版者・発行元：最新医学社  

CiNii Books

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記述言語：日本語   出版者・発行元：医歯薬出版(株)  

Global Human Proteome Projectが掲げるプロテオーム研究戦略として、質量分析基盤、抗体基盤、データベース・バイオインフォマティクス基盤プロテオミクスが位置づけられている。なかでも抗体基盤プロテオミクスは、疾患の原因究明や個別化医療に向けたバイオマーカー探索において有用であると報告されている。しかし、バイオマーカー候補タンパク質を多数検体で迅速に検証するための技術基盤はいまだ整備されておらず、探索から検証にかけて律速である問題も明らかになっている。そこで本稿では、創薬標的・バイオマーカー探索から検証までをスムースにつなげるプラットフォームとして、著者らが行っている質量分析基盤と抗体基盤の両プロテオミクスを融合したアレイ基盤プロテオミクス解析について紹介する。(著者抄録)

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ELSEVIER SCIENCE INC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2014-4070

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本口腔科学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：OXFORD UNIV PRESS  

DOI： 10.1093/annonc/mdu358.44

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

DOI： 10.11241/jsmtmr.29.9

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：(一社)日本呼吸器学会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

DOI： 10.11241/jsmtmr.29.7

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記述言語：日本語   出版者・発行元：日本臨床プロテオーム研究会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本肺癌学会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(公社)日本生化学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：日本語   出版者・発行元：日本臨床検査医学会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：(一社)日本動脈硬化学会  

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記述言語：日本語   出版者・発行元：(一社)日本細胞生物学会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：日本臨床プロテオーム研究会  

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記述言語：日本語   出版者・発行元：日本臨床プロテオーム研究会  

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記述言語：日本語   出版者・発行元：(公社)日本生化学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：OXFORD UNIV PRESS  

DOI： 10.1093/annonc/mds564

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記述言語：日本語   出版者・発行元：日本臨床外科学会  

DOI： 10.3919/jjsa.73.816

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記述言語：日本語   出版者・発行元：(一社)日本癌治療学会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

J-GLOBAL

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：OXFORD UNIV PRESS  

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記述言語：日本語   出版者・発行元：(一社)日本口腔腫瘍学会  

がん臨床において転移は重要な予後因子のひとつである。分子レベルでの転移機構の解明が望まれている。転移には細胞の運動能が深く関わっており、細胞運動を制御する因子のひとつとしてアクチン細胞骨格のダイナミックな変化があげられる。われわれはアクチン線維を束状化するアクチニン-4(actinin-4、遺伝子名:ACTN4)を単離し、本分子の発現が細胞突起形成と運動能亢進に関与することを明らかにしてきた。臨床病理学的には、アクチニン-4タンパク質の発現の上昇が浸潤性乳管がんの予後を規定するだけでなく、大腸がんのリンパ節転移にも相関した。肺小細胞がんからはがん精巣抗原として新規スプライスバリアントが単離され、診断マーカーとしての応用も考えられている。また最近では、actinin-4タンパク質の増加がACTN4の遺伝子増幅に起因することが明らかになり、ACTN4遺伝子増幅が卵巣がん、膵がんの症例で認められている。本総説では、がん転移・浸潤に対するアクチニン-4の生物学的役割について述べる。(著者抄録)

DOI： 10.5843/jsot.24.95

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J02382&link_issn=&doc_id=20120919280004&doc_link_id=%2Fdy8ortum%2F2012%2F002403%2F005%2F0095-0101%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdy8ortum%2F2012%2F002403%2F005%2F0095-0101%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：OXFORD UNIV PRESS  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：OXFORD UNIV PRESS  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：OXFORD UNIV PRESS  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：OXFORD UNIV PRESS  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本泌尿器科学会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

DOI： 10.11241/jsmtmr.27.9

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その他リンク： http://search.jamas.or.jp/link/ui/2013231553

記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

DOI： 10.11241/jsmtmr.27.57

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その他リンク： http://search.jamas.or.jp/link/ui/2013231577

記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：日本臨床プロテオーム研究会  

DOI： 10.14905/jscp.2012.0_20

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：(株)東京医学社  

・腫瘍マーカーは腫瘍細胞などより産生され、患者の組織、血液などの体液、排泄物(尿、便)などに検出されるさまざまな物質であり、腫瘍の検出や鑑別診断、病期分類、治療効果の判定や治療後の経過観察(モニタリング)などの補助に広く臨床検査として利用されている。・バイオマーカー(biomarker)は従来の腫瘍マーカーより広い意味で定義された診断指標であり、予後予測バイオマーカー(prognostic biomarker)、治療効果・副作用予測バイオマーカー(predictive biomarker)などとして応用されている。・代理バイオマーカー(surrogate biomarker)やコンパニオンバイオマーカー(companion biomarker)は臨床試験期間の短縮や、医薬品開発コストの削減に貢献している。・国内外に腫瘍マーカーやバイオマーカーを実用化するための、支援機関が整備され始めた。(著者抄録)

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：(一社)日本医用マススペクトル学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本消化器外科学会  

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記述言語：日本語   出版者・発行元：(株)文光堂  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM10-4580

Web of Science

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：日本臨床外科学会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ELSEVIER SCIENCE BV  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本外科学会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：日本語   出版者・発行元：(株)日本臨床社  

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2009113780

記述言語：日本語   出版者・発行元：尿路悪性腫瘍研究会  

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：日本語   出版者・発行元：西日本泌尿器科学会  

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記述言語：日本語   出版者・発行元：(株)医薬ジャーナル社  

バイオマーカーは生体材料に存在する計測可能な客観的指標であり、バイオマーカーの開発に当たっては、無数にある生体物質から有用な物質を見つけ出す探索過程(discovery phase)と見つけた物質が真に臨床的に有用であるかを検証する過程(validation phase)の2つの大きな過程が存在する。本稿ではわれわれが行っている手法を例示し、癌診断治療のバイオマーカー開発の現況を解説する。(著者抄録)

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2009006298

記述言語：日本語   出版者・発行元：日本電気泳動学会  

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記述言語：英語   出版者・発行元：(一社)日本細胞生物学会  

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記述言語：日本語   出版者・発行元：(一社)日本外科学会  

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記述言語：英語   出版者・発行元：Yamaguchi University School of Medicine  

Alpha-actinin-4, originally identified as an actin-binding protein, has been associated with cell motility and cancer invasion. However, it forms complexes with a diverse array of partner proteins and is speculated to exert several distinct functions based on the characteristics of these proteins. Immunoprecipitation and mass spectrometric analysis reveal that alpha-actinin-4 forms native complexes with several partner proteins in 22RV1 cells, including β/γ-actin, clathrin heavy chain and nonmuscular myosin heavy chain. Clathrin is a coat protein that covers the internalized membrane pit and plays a central role in early endocytosis. We identified other clathrin-related and unrelated cargo proteins, including dynamin, adaptin-γ, β-NAP and p47A, that interact with alpha-actinin-4. Immunofluorescence microscopy revealed that dynamin and clathrin are co-localized with alpha-actinin-4 at the dorsal sites of membrane rufflings, and the transfection of ACTN4 cDNA facilitates the transport of transferrin into the peri-nuclear endosomes. In this review, we report that alpha-actinin-4 is involved in the regulation of endocytosis. Endocytosis enforces termination of signalling evoked by the cell surface receptors and regulates recycling of receptors and ligands. The change of alpha-actinin-4 expression levels may therefore induce aberrations in the intracellular trafficking of various cell surface molecules, such as growth factors and receptors.

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その他リンク： http://search.jamas.or.jp/link/ui/2009201054

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：IOS PRESS  

Web of Science

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記述言語：日本語   出版者・発行元：(株)羊土社  

昨今、質量分析を用いた血清・血漿タンパク質ダイレクトプロファイル法による診断マーカーの開発が注目を集めている。われわれは、膵癌血漿診断マーカー開発を目的に245例の血漿検体をSELDI-QqTOF-MS(surface-enhanced laser desorption/ionization coupled with hybrid quadrupole time-flight mass spectrometry)法を用いて、ダイレクトタンパク質プロファイルを行った。4本のペプチドピーク情報から、学習セット、検証セットともに90%以上の判別率で膵癌の判定する判別モデルの導出に成功した。本稿では実用化の可能性を含めて論じたいと思う。(著者抄録)

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：BLACKWELL PUBLISHING  

Web of Science

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記述言語：日本語   出版者・発行元：東京医科大学医学会  

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その他リンク： http://search.jamas.or.jp/link/ui/2008074582

記述言語：日本語   出版者・発行元：(株)先端医学社  

Wntシグナル経路の伝達因子であるβ-カテニンは細胞内に蓄積することによって前癌病変である腺腫発生に関与していることが考えられている。そこで、蓄積したβ-カテニンが転写因子であるT-cell factor(TCF)4に結合することにより細胞内で発現変動する蛋白質を同位体標識(ICAT)法にて網羅的に検索し、腸上皮の分化により誘導されβ-カテニン/TCF4と複合体形成をするスプライシングファクター1(SF1)を同定した。SF1は転写および細胞増殖抑制のみならず、癌特異的選択的スプライシングを制御することからその異常が発癌過程に重要な役割を果たしていることが考えられる。(著者抄録)

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記述言語：日本語   出版者・発行元：日本電気泳動学会  

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記述言語：日本語   出版者・発行元：(株)医薬ジャーナル社  

膵がんは、予後不良な固形がんのひとつである。膵がんを高精度に検出できる血漿マーカーがあれば、予後を改善できる可能性がある。近年、血液中のタンパク質を網羅的に解析するプロテオミクス分析技術が進歩し、血漿ペプチドプロファイルによるがん検出法の開発が注目を集めている。われわれは、本方法を用いて、膵がん血漿マーカーの開発を行ってきた。本稿では、現在までの進捗状況と、今後の実用化に向けた取り組みについて概説する。(著者抄録)

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2007341611

記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：英語   出版者・発行元：日本癌学会  

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記述言語：日本語   出版者・発行元：(公社)日本生化学会