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Overexpression of the receptor tyrosine kinase EphA4 in human gastric cancers

World Journal of Gastroenterology 2008年第37期14卷 5650-5656页

作者： Mariko Oki Hiroyuki Yamamoto Hiroaki Taniguchi yasushi adachi Kohzoh Imai Yasuhisa Shinomura First Department of Internal Medicine Sapporo Medical University School of MedicineSapporo 060-8543 Japan Sapporo Medical University Sapporo 060-8556 Japan

AIM: To clarify the expression and role of Ephrin receptor A4 (EphA4) in gastric cancer in relation to clinicopathological characteristics and the expression of fibroblast growth factor receptor 1 (FGFR1) and ephrin ligands. METHODS: Eleven gastric carcinoma cell lines, 24 paired surgical fresh specimens of gastric adenocarcinoma and adjacent nontumor tissue, 74 conventional formalin-fixed, paraffin-embedded tumor specimens, and 55 specimens spotted on tissue microarray (TMA) were analyzed. Reverse transcription-PCR (RT-PCR), real-time RT-PCR, immunohistochemistry, and cell growth assays were performed. RESULTS: Overexpression of EphA4 mRNA expres-sion was observed in 8 (73%) of 11 gastric cancer cell lines and 10 (42%) of 24 gastric cancer tissues. Over-expression of EphA4, analyzed by immunohistochemistry, was observed in 62 (48%) of 129 gastric cancer tissues. EphA4 overexpression, at the protein level, was significantly associated with depth of invasion and recurrence. EphA4 overexpression was also correlated with FGFR1 overexpression. Patients with EphA4-positive cancer had significantly shorter overall survival periods than did those with EphA4-negative cancer (P = 0.0008). The mRNAs for ephrin ligands were coexpressed in various combinations in gastric cancer cell lines and cancer tissues. Downregulation of EphA4 expression by siRNA in EphA4-overexpressing gastric cancer cell lines resulted in a significant decrease in cell growth. CONCLUSION: Our results suggest that overexpres-sion of EphA4 plays a role in gastric cancer.

关键词： Ephrin receptor A4 Gastric cancer Ephrin Fibroblast growth factor receptor 1 Prognosis

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Interrelationship between microsatellite instability and microRNA in gastrointestinal cancer

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World Journal of Gastroenterology 2012年第22期18卷 2745-2755页

作者： Hiroyuki Yamamoto yasushi adachi Hiroaki Taniguchi Hiroaki Kunimoto Katsuhiko Nosho Hiromu Suzuki Yasuhisa Shinomura First Department of Internal Medicine Sapporo Medical University School of Medicine Division of Cancer Cell Research Institute of Medical Science University of Tokyo Department of Molecular Biology Sapporo Medical University School of Medicine

There is an increasing understanding of the roles that microsatellite instability （MSI） plays in Lynch syndrome （by mutations） and sporadic （by mainly epigenetic changes） gastrointestinal （GI） and other cancers. Defi- cient DNA mismatch repair （MMR） results in the strong mutator phenotype known as MSI, which is the hall- mark of cancers arising within Lynch syndrome. MSI is characterized by length alterations within simple repeated sequences called microsatellites. Lynch syn- drome occurs primarily because of germline mutations in one of the MMR genes, mainly MLH1 or MSH2, less frequently MSH6, and rarely PMS2. MSI is also observed in about 15% of sporadic colorectal, gastric, and en-dometrial cancers and in lower frequencies in a minor- ity of other cancers where it is often associated with the hypermethylation of the IVlLH1 gene. miRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level and are critical in many biological processes and cellular pathways. There is accumulating evidence to support the notion that the interrelationship between MSI and miRNA plays a key role in the pathogenesis of GI cancer. As a possible new mechanism underlying MSI, overexpression of m/R-IEE has been shown to downregulate expression of MLH1, IVlSH2, and MSH6. Thus, a subset of MSI-positive （MSI＋） cancers without known MMR defects may result from m/R-1E5 overexpression. Target genes of frameshift mutation for MSI are involved in various cellular func- tions, such as DNA repair, cell signaling, and apoptosis. A novel class of target genes that included not only epi- genetic modifier genes, such as HDAC2, but also miRNA processing machinery genes, including TARBP2 and XPO5, were found to be mutated in MSI＋ GI cancers. Thus, a subset of MSI＋ colorectal cancers （CRCs） has been proposed to exhibit a mutated miRNA machinery phenotype. Genetic, epigenetic, and transcriptomic dif- ferences exist between MSI＋ and MSI- cancers. Mo- lecular signatures of miR

关键词： Microsatellite instability MicroRNA DNA mis-match repair Frameshiff mutation MicroRNA processing

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A candidate targeting molecule of insulin-like growth factor-Ⅰ receptor for gastrointestinal cancers

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World Journal of Gastroenterology 2010年第46期16卷 5779-5789页

作者： yasushi adachi Hiroyuki Yamamoto Hirokazu Ohashi Takao Endo David P Carbone Kohzoh Imai Yasuhisa Shinomura First Department of Internal Medicine Sapporo Medical University Department of Internal Medicine Sapporo Shirakabadai Hospital Vanderbilt-Ingram Cancer Center and Departments of Medicine and Cell Biology Vanderbilt University

Advances in molecular research in cancer have brought new therapeutic strategies into clinical *** new group of targets is tyrosine kinase receptors,which can be treated by several strategies,including small molecule tyrosine kinase inhibitors(TKIs) and monoclonal antibodies(mAbs).Aberrant activation of growth factors/receptors and their signal pathways are required for malignant transformation and progression in gastrointestinal(GI) *** concept of targeting specif ic carcinogenic receptors has been validated by successful clinical application of many new *** I insulin-like growth factor(IGF) receptor(IGF-IR) signaling potently stimulates tumor progression and cellular differentiation,and is a promising new molecular target in human *** this review,we focus on this promising therapeutic target,*** IGF/IGF-IR axis is an important modifier of tumor cell proliferation,survival,growth,and treatment sensitivity in many malignant diseases,including human GI *** studies demonstrated that downregulation of IGF-IR signals reversed the neoplastic phenotype and sensitized cells to anticancer *** results were mainly obtained through our strategy of adenoviruses expressing dominant negative IGF-IR(IGF-IR/dn) against gastrointestinal cancers,including esophagus,stomach,colon,and *** also summarize a variety of strategies to interrupt the IGFs/IGF-IR axis and their preclinical *** mAbs and TKIs targeting IGF-IR have entered clinical trials,and early results have suggested that these agents have generally acceptable safety profiles as single *** summarize the advantages and disadvantages of each strategy and discuss the merits/demerits of dual targeting of IGF-IR and other growth factor receptors,including Her2 and the insulin receptor,as well as other alternatives and possible drug ***,IGF-IR might be a candidate for a molecular therapeutic target in human GI carcino

关键词： Dominant negative Gastrointestinal cancer Insulin like growth factor-I receptor Monoclonal anti-body Tyrosine kinase inhibitor

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Overexpression of β3/γ2 chains of laminin-5 and MMP7 in biliary cancer

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World Journal of Gastroenterology 2009年第31期15卷 3865-3873页

作者： Toshikuni Oka Hiroyuki Yamamoto Shigeru Sasaki Masanori Ii Keiichi Hizaki Hiroaki Taniguchi yasushi adachi Kohzoh Imai Yasuhisa Shinomura First Department of Internal Medicine Sapporo Medical University School of Medicine Sapporo Medical University

AIM： To clarify the clinicopathological significance of laminin-5 y2 （LNγ2） and 133 （LNI33） chains and MMP7 expression in biliary tract cancer. METHODS： We analyzed the association between immunohistochemically detected LNγ2, LNβ3, and MMP7 expression in biliary tract cancer and clinicopathological characteristics. Activity of MMP7 was analyzed by casein zymography. An in vitro invasion assay after treatment with MMP7-specific siRNA was performed. RESULTS： LNγ2 expression was predominantly observed in carcinoma cells at the invasive front. LNγ2 expression was seen in 57% of patients with biliary tract cancer, and was associated with depth of invasion, histologic type, and advanced stage. The expression pattern of LNβ3 was classified Into two types： invasive front dominant type （38%） and diffuse type （28%）.The invasive front dominant type was associated with histologic type and advanced stage. MMP7 positivity was correlated with LNγ2 or LNβ3 expression but not with clinicopathological characteristics. Active MMP7 detected by casein zymography was correlated with depth of invasion and advanced stage. Downregulation of MMP7 expression by siRNA resulted in a significant decrease in biliary tract cancer cell invasion in ***： Our results suggest that LNγ2 and LNβ3, in conjunction with MMP7, play a key role in the progression of biliary tract cancer.

关键词： Biliary tract cancer Laminin-5 Laminin γ2 Laminin β3 MMP7

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Genetic and epigenetic characteristics of gastric cancers with JC virus T-antigen

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World Journal of Gastroenterology 2009年第44期15卷 5579-5585页

作者： Satoshi Yamaoka Hiroyuki Yamamoto Katsuhiko Nosho Hiroaki Taniguchi yasushi adachi Shigeru Sasaki Yoshiaki Arimura Kohzoh Imai Yasuhisa Shinomura First Department of Internal Medicine Sapporo Medical UniversitySapporo 060-8543 Japan Sapporo Medical University Sapporo 060-8556 Japan

AIM： To clarify the significance of JC virus （JCV） T-antigen （T-Ag） expression in human gastric cancer. METHODS： We investigated the relationship between TAg detected by immunohistochemistry and Epstein- Barr virus （EBV） infection, microsatellite instability （MSI）, and genetic and epigenetic alterations in gastric cancers. Mutations in the p53,β-catenin, K/MS, BRAF, PIK3CA genes were analyzed by PCR- single strand conformation polymorphism and DNA sequencing. Allelic losses were determined by PCR at 7 microsatellite loci. Aberrant DNA methylation was analyzed by MethyLight assay. RESULTS： JCV T-Ag protein expression was found in 49% of 90 gastric cancer tissues. TAg positivity was not correlated with clinicopathological characteristics. TAg expression was detected in a similar percentage of EBV positive cancers （4 of 9, 44%） and EBV negative cancers （35 of 73, 48%）. TAg expression was detected in a significantly lower percentage of MSI-H cancers （14%） than in non MSI-H cancers （55%, P = 0.005）. TAg expression was detected in a significantly higher percentage of cancers with nuclear/cytoplasmic localization of β-catenin （15 of 21, 71%） than in cancers without （42%, P = 0.018）. p53 mutations were detected in a significantly lower percentage of T-Ag positive cancers （32%） than in TAg negative cancers （57%, P = 0.018）. TAg positive gastric cancers showed a significant increase in the allelic losses and aberrant methylation compared with T-Ag negative gastric cancers （P = 0.008 and P = 0.003）. CONCLUSION： The results suggest that JCV T-Ag is involved in gastric carcinogenesis through multiple mechanisms of genetic and epigenetic alterations.

关键词： JC virus T-antigen Epstein-Barr virus Microsatellite instability Gastric cancer

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Hepatic portal venous gas in pancreatic solitary metastasis from an esophageal squamous cell carcinoma

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Hepatobiliary & Pancreatic Diseases International 2013年第1期12卷 103-105页

作者： Takeshi Sawada yasushi adachi Manabu Noda Kimishige Akino Takefumi Kikuchi Hiroaki Mita Yoshifumi Ishii Takao Endo Division of Gastroenterology Sapporo Shirakaba-dai Hospital Department of Pathology Sapporo Shirakaba-dai Hospital

BACKGROUND:Hepatic portal venous gas(HPVG) is a rare entity commonly associated with intestinal necrosis and fatal outcome,and various underlying diseases have been *** solitary metastasis without local extension is also rare in esophageal squamous cell ***:This report describes an interesting and unusual case of HPVG arising from pancreatic *** revealed pathogenesis of HPVG and synchronous tumors of the esophagus and ***:A 73-year-old man developed synchronous double tumor in the esophagus and pancreas several months before acute abdomen and his death,which were generated by *** revealed that HPVG was caused by gastric wall infarction owing to expansion of an isolated pancreatic metastasis from esophageal squamous cell ***:This is the first case of HPVG that was derived from pancreatic tumor *** he had been diagnosed with solitary pancreatic metastasis from esophageal squamous cell carcinoma in the first time,he might have an option for chemotherapy,which could let him live longer.

关键词： hepatic portal venous gas solitary pancreatic tumor metastasis

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Transcriptional silencing of Dickkopf gene family by CpG island hypermethylation in human gastrointestinal cancer

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World Journal of Gastroenterology 2008年第17期14卷 2702-2714页

作者： Tadateru Maehata Hiroaki Taniguchi Hiroyuki Yamamoto Katsuhiko Nosho yasushi adachi Nobuki Miyamoto Chie Miyamoto Noriyuki Akutsu Satoshi Yamaoka Fumio Itoh Department of Gastroenterology and Hepatology St. Marianna University School of Medicine First Department of Internal Medicine Sapporo Medical University

AIM： To clarify alterations of Dickkopfs （Dkks） and Kremen2 （Krm2） in gastrointestinal cancer. METHODS： We investigated the expression profiles and epigenetic alterations of Dkks and Krm2 genes in gastrointestinal cancer using RT-PCR, tissue microarray analysis, and methylation specific PCR （MSP）. Cancer cells were treated with the demethylating agent and/or histone deacetylase inhibitor. WST-8 assays and/n y/tro invasion assays after treatment with specific siRNA for those genes were performed. RESULTS： Dkks and Krm2 expression levels were reduced in a certain subset of the gastrointestinal cancer cell lines and cancer tissues. This was correlated with promoter hypermethylation. There were significant correlations between Dkks over-expression levels and beta-catenin over-expression in colorectal cancer. In colorectal cancers with beta-catenin over-expression, Dkk-1 expression levels were significantly lower in those with lymph node metastases than in those without. Down-regulation of Dkks expression by siRNA resulted in a significant increase in cancer cell growth and invasiveness in vitro.CONCLUSION： Down-regulation of the Dkks associated to promoter hypermethylation appears to be frequently involved in gastrointestinal tumorigenesis.

关键词： Dickkopf genes Kremen2 gene Methylation Wnt signaling Gastrointestinal cancer

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Insulin-like growth factor-1, IGF binding protein-3, and the risk of esophageal cancer in a nested case-control study

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World Journal of Gastroenterology 2017年第19期23卷 3488-3495页

作者： yasushi adachi Masanori Nojima Mitsuru Mori Kentaro Yamashita Hiro-o Yamano Hiroshi Nakase Takao Endo Kenji Wakai Kiyomi Sakata Akiko Tamakoshi Division of Gastroenterology Department of Internal MedicineSapporo Shirakaba-dai Hospital Department of Gastroenterology Sapporo Medical University The Institute of Medical Science Hospital The University of Tokyo Department of Public Health Sapporo Medical UniversitySchool of Medicine Department of Preventive Medicine Nagoya UniversityGraduate School of Medicine Department of Hygiene and Preventive Medicine Iwate Medical University School of Medicine Department of Public Health Hokkaido University School of Medicine

To assess the relationship between serum levels of insulin-like growth factor-1 (IGF1)/IGF-binding protein-3 (IGFBP3) and the risk of esophageal *** assessed the relationship between the serum levels of these molecules and the risk of esophageal cancer in a prospective, nested case-control study of participants from the Japan Collaborative Cohort Study. A baseline survey was conducted from 1988 to 1990. Of the 110585 enrolled participants, 35% donated blood samples. Those who had been diagnosed with esophageal cancer were considered cases for nested case-control studies. A conditional logistic model was used to estimate odds ratios for the incidence of esophageal cancer associated with serum IGF1 and IGFBP3 ***-one cases and 86 controls were eligible for the present assessment. The molar ratio of IGF1/IGFBP3, which represents the free and active form of IGF1, was not correlated with the risk of esophageal carcinoma. A higher molar difference between IGFBP3 and IGF1, which estimates the free form of IGFBP3, was associated with a decreased risk of esophageal carcinoma (P = 0.0146), and people in the highest tertile had the lowest risk (OR = 0.107, 95%CI: 0.017-0.669). After adjustment for body mass index, tobacco use, and alcohol intake, the molar difference of IGFBP3-IGF1 was inversely correlated with the risk of esophageal carcinoma (P = 0.0150).CONCLUSIONThe free form of IGFBP3, which is estimated by this molar difference, may be inversely associated with esophageal cancer incidence.

关键词： Esophageal cancer Insulin-like growth factor Insulin-like growth factor binding protein Nested case-control study Odds ratio

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Genomic characterization of esophageal squamous cellcarcinoma:insights from next-generation sequencing

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World Journal of Gastroenterology 2016年第7期22卷 2284-2293页

作者： yasushi Sasaki Miyuki Tamura Ryota Koyama Takafumi Nakagaki yasushi adachi Takashi Tokino Department of Medical Genome Sciences Research Institute for Frontier MedicineSapporo Medical UniversitySapporo 060-8556Japan Department of Gastroenterology Rheumatology and Clinical ImmunologySapporo Medical University School of MedicineSapporo 060-8543Japan

Two major types of cancer occur in the esophagus: squamous cell carcinoma, which is associated with chronic smoking and alcohol consumption, and adenocarcinoma, which typically arises in gastric reflux-associated Barrett's esophagus. Although there is increasing incidence of esophageal adenocarcinoma in Western counties, esophageal squamous cell carcinoma(ESCC) accounts for most esophageal malignancies in East Asia, including China and Japan. Technological advances allowing for massively parallel, high-throughput next-generation sequencing(NGS) of DNA have enabled comprehensive characterization of somatic mutations in large numbers of tumor samples. Recently, several studies were published in which whole exome or whole genome sequencing was performed in ESCC tumors and compared with matched normal DNA. Mutations were validated in several genes, including in TP53, CDKN2 A, FAT1, NOTCH1, PIK3 CA, KMT2 D and NFE2L2, which had been previously implicated in ESCC. Several new recurrent alterations have also been identified in ESCC. Combining the clinicopathological characteristics of patients with information obtained from NGS studies may lead to the development of effective diagnostic and therapeutic approaches for ESCC. As this research becomes more prominent, it is important that gastroenterologist become familiar with the various NGS technologies and the results generated using these methods. In the present study, we describe recent research approaches using NGS in ESCC.

关键词： esophageal squamous cell carcinoma next-generation sequencing somatic mutation Drivermutation copy number variant

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Alterations in the human epidermal growth factor receptor 2-phosphatidylinositol 3-kinase-v-Akt pathway in gastric cancer

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World Journal of Gastroenterology 2012年第45期18卷 6577-6586页

作者： Yasutaka Sukawa Hiroyuki Yamamoto Katsuhiko Nosho Hiroaki Kunimoto Hiromu Suzuki yasushi adachi Mayumi Nakazawa Takayuki Nobuoka Mariko Kawayama Masashi Mikami Takashi Matsuno Tadashi Hasegawa Koichi Hirata Kohzoh Imai Yasuhisa Shinomura First Department of Internal Medicine Sapporo Medical University School of MedicineSapporo 60-8543Japan Department of Molecular Biology Sapporo Medical University School of MedicineSapporo 60-8543Japan First Department of Surgery Sapporo Medical University School of MedicineSapporo 60-8543Japan Department of Gastroenterology JR Sapporo HospitalSapporo 60-8543Japan Department of Surgery Sapporo Gekakinen HospitalSapporo 60-8543Japan Department of Surgical Pathology Sapporo Medical University HospitalSapporo 60-8543Japan Division of Cancer Research The Institute of Medical ScienceThe University of TokyoTokyo 108-8639Japan

AIM:To investigate human epidermal growth factor receptor 2(HER2)-phosphatidylinositol 3-kinase(PI3K)-vAkt murine thymoma viral oncogene homolog signaling ***:We analyzed 231 formalin-fixed,paraffinembedded gastric cancer tissue specimens from Japanese patients who had undergone surgical *** patients' age,sex,tumor location,depth of invasion,pathological type,lymph node metastasis,and pathological stage were determined by a review of the medical *** of HER2 was analyzed by immunohistochemistry(IHC) using the HercepTest TM *** criteria for HER2 positivity(0,1+,2+,and 3+) were *** that scored 3+ were considered *** of phospho Akt(pAkt) was also analyzed by *** were considered pAkt-positive when the percentage of positive tumor cells was 10% or ***3K,catalytic,alpha polypeptide(PIK3CA) mutations in exons 1,9 and 20 were analyzed by ***-Barr virus(EBV) infection was analyzed by in situ hybridization targeting EBV-encoded small RNA(EBER) with an EBER-RNA *** instability(MSI) was analyzed by polymerase chain reaction using the mononucleotide markers BAT25 and ***:HER2 expression levels of 0,1+,2+ and 3+ were found in 167(72%),32(14%),12(5%) and 20(8.7%) samples,***2 overexpression(IHC 3+) significantly correlated with intestinal histological type(15/20 vs 98 /205,P = 0.05).PIK3CA mutations were present in 20 cases(8.7%) and significantly correlated with MSI(10/20 vs 9/211,P < 0.01).The mutation frequency was high(21%) in T4 cancers and very low(6%) in T2 *** in exons 1,9 and 20 were detected in 5(2%),9(4%) and 7(3%) cases,*** new types of PIK3CA mutation,R88Q and R108H,were found in *** PIK3CA mutations were heterozygous missense singlebase substitutions,the most common being H1047R(6/20,30%) in *** cancers(8%) were EBV-positive and this positivity significantly correlated with a diffu

关键词： Human epidermal growth factor receptor 2 Phosphatidylinositol 3-kinase Catalytic Alpha polypep-tide Epstein-Barr virus Aid: Gastric cancer

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