miR-1271低表达激活IGF1R/IRS1信号通路在胃癌细胞耐药中的机制研究

项目名称： miR-1271低表达激活IGF1R/IRS1信号通路在胃癌细胞耐药中的机制研究

项目编号： No.81201705

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 朱伟

作者单位： 南京医科大学

项目金额： 23万元

中文摘要： miRNA表达异常可以通过多种途径参与胃癌细胞耐药。课题组研究发现：miR-1271在三种胃癌耐药细胞（SGC7901/DDP、SGC7901/5-FU、SGC7901/VCR）和耐药患者血浆中均呈显著低表达，上调miR-1271可增加耐药细胞对化疗药物的敏感性。miR-1271在三种胃癌耐药细胞中低表达的机制不同，在SGC7901/DDP和SGC7901/5-FU细胞中，其低表达可能是c-Myc抑制的结果，而在SGC7901/VCR细胞中其低表达与其启动子CpG岛超甲基化有关。miR-1271低表达可能靶向激活IGF1R/IRS1信号通路介导胃癌细胞的耐药。课题组应用胃癌细胞株、胃癌患者血浆、组织及具有肿瘤微环境的SCID小鼠荷瘤模型，从细胞、临床样本和体内实验三个层面研究miR-1271在胃癌细胞耐药中的调控机制，为miRNA调控逆转胃癌耐药的研究奠定实验基础和提供重要信息。

中文关键词： 胃癌；顺铂耐药；miRNA；信号通路；肿瘤标记物

英文摘要： Studies showed that drug resistance of gastric cancer cells could be modulated by the abnormal expression of miRNAs which targeted multiple cell signal pathways. Our research found that miR-1271 was down-regulated in three drug-resistant gastric cancer cells (SGC7901/DDP、SGC7901/5-FU、SGC7901/VCR)and plasma of drug-resistant patients, overexpression of miR-1271 sensitized drug-resistant cells to anti-cancer drugs. The regulatory mechanism of the downregulation of miR-1271 in three drug-resistant gastric cancer cells was different. In SGC7901/DDP and SGC7901/5-FU cells, miR-1271 might be mainly inhibited by c-Myc, while in SGC7901/VCR cells hypermethylation of CpG island in miR-1271 promoter might be the cause of its lower expression level. The downregulation of miR-1271 could further activate IGF1R/IRS1 pathway which was involved in drug resistance of gastric cancer cells, via targeting their 3'UTR. We will study the regulation mechanism of miR-1271 in drug resistant gastric cancer in the level of cell (gastric cancer cell lines), clinical specimen (the plasma and tissue of patients with gastric cancer) and in vivo experiment (cancer microenvironment SCID mice bearing tumor model) to provide more information and details of the reversal of drug resistance of gastric cancer by regulating the expression of miRNAs.

英文关键词： gastric cancer；cisplatin resistance；miRNA；signal pathway；cancer biomarker