Santos Juliana C, Brianti Mitsue T, Almeida Victor R, Ortega Manoela M, Fischer Wolfgang, Haas Rainer, Matheu Ander, Ribeiro Marcelo L
Clinical Pharmacology and Gastroenterology Unit, São Francisco University Medical School, São Francisco University, Bragança Paulista, São Paulo, Brazil.
Women's Integrated Healthcare Center (CAISM), State University of Campinas, (UNICAMP) Campinas, São Paulo, Brazil.
Mol Carcinog. 2017 Apr;56(4):1372-1379. doi: 10.1002/mc.22590. Epub 2016 Nov 23.
Genetic and epigenetic inactivation of DNA mismatch repair (MMR) genes might lead to modifications in cancer-related gene expression and cancer development. Recently, it has been shown that the infection by Helicobacter pylori, the major causative agent of gastric cancer, induces DNA damage and inhibits MMR DNA repair. Also, it has been reported that microRNAs (miRs) have an important role in regulating genomic stability and MMR DNA repair. Thus, the aim of this study was to identify miRs regulating MMR pathway in H. pylori-associated gastric carcinogenesis. To address this question, a gastric epithelial cell line and AGS cancer gastric cells were infected with several H. pylori strains. MMR gene expression and miRs correlating with H. pylori strain infection were evaluated. The results showed that H. pylori infection significantly down-regulated the expression of all selected MMR genes. Also, H. pylori infection modulated the expression of several miRs (including miR-150-5p, miR-155-5p, and miR-3163), after 4, 8, and 12 h of infection. Computational prediction of candidate miRs and their predicted MMR targeting sites were obtained from TargetScan, mirDB, and MetaCore. The generated data indicated that the selected miRs (miR-150-5p, miR-155-5p, and miR-3163) could possibly target and modulate MMR genes (POLD3, MSH2, and MSH3, respectively). The target validation was performed using mimics and luciferase gene reporter assays. Briefly, this study shows that H. pylori impairs MMR DNA repair pathway and identifies miRs that regulate MMR gene expression in gastric cancer. © 2016 Wiley Periodicals, Inc.
DNA错配修复（MMR）基因的遗传和表观遗传失活可能导致癌症相关基因表达的改变以及癌症的发生发展。最近的研究表明，胃癌的主要致病因子幽门螺杆菌感染可诱导DNA损伤并抑制MMR DNA修复。此外，有报道称微小RNA（miRs）在调节基因组稳定性和MMR DNA修复中起重要作用。因此，本研究的目的是鉴定在幽门螺杆菌相关胃癌发生过程中调节MMR途径的miRs。为了解决这个问题，用几种幽门螺杆菌菌株感染了胃上皮细胞系和AGS胃癌细胞。评估了与幽门螺杆菌菌株感染相关的MMR基因表达和miRs。结果表明，幽门螺杆菌感染显著下调了所有选定MMR基因的表达。此外，在感染4、8和12小时后，幽门螺杆菌感染调节了几种miRs（包括miR-150-5p、miR-155-5p和miR-3163）的表达。从TargetScan、mirDB和MetaCore获得候选miRs及其预测的MMR靶向位点的计算预测结果。生成的数据表明，选定的miRs（miR-150-5p、miR-155-5p和miR-3163）可能分别靶向并调节MMR基因（POLD3、MSH2和MSH3）。使用模拟物和荧光素酶基因报告试验进行了靶点验证。简而言之，本研究表明幽门螺杆菌损害MMR DNA修复途径，并鉴定了在胃癌中调节MMR基因表达的miRs。©2016威利期刊公司。
