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Interrelationship between microsatellite instability and microRNA in gastrointestinal cancer

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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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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