长链非编码RNA n385229吸附miR-497对胰腺癌化疗耐药表型的调控作用

项目名称： 长链非编码RNA n385229吸附miR-497对胰腺癌化疗耐药表型的调控作用

项目编号： No.81502051

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 徐建威

作者单位： 山东大学

项目金额： 18万元

中文摘要： 胰腺癌化疗耐药机制是目前研究的热点和难点。我们前期研究发现miR-497负向调控IGF-1R和FGFR1，参与胰腺癌化疗敏感性调控，部分成果已发表至Oncotarget杂志；生物信息学分析发现lncRNA-n385229序列上有多个miR-497种子区的结合位点，下调lncRNA-n385229，促进miR-497表达，降低IGF-1R和FGFR1的蛋白表达水平。因此，我们推测：lncRNA-n385229作为ceRNA，竞争性结合miR-497，进而调控miR-497靶基因（IGF-1R、FGFR1）的表达水平，从而参与胰腺癌化疗耐药表型的调控。本课题拟通过体内外实验探索lncRNA-n385229/miR-497/（IGF-1R、FGFR1）对胰腺癌吉西他滨化疗敏感性的调控作用及调控机制；并结合临床标本，明确lncRNA-n385229/miR-497评估化疗敏感性、及判断预后的价值。

中文关键词： 胰腺外分泌肿瘤；化疗耐药；长链非编码RNA；竞争性内源RNA；miRNA

英文摘要： Chemoresistance is one of the key and the difficult subject of pancreatic cancer research. The mechanism of drug-resistance of pancreatic cancer remains unclear. Our previous study indicated that miR-497 re-sensitized pancreatic cancer cells to gemcitabine through direct downregulation of IGF-1R and FGFR1 protein expression, which had been partly published on Oncotarget. Bioinformatic analysis revealed the putative complementary sequences for the seed region of mir-497 in lncRNA-n385229. In addition, downregulation of lncRNA-n385229 significantly increased miR-497 expression levels, decreased the protein levels of IGF-1R and FGFR1, and re-sensitized cells to gemcitabine treatment. Based on our previous studies and literatures review, we speculated that lncRNA-n385229 might be a ceRNA and acted as a miR-497 sponge to involve in regulating chemoresistance of pancreatic cancer. This study will investigate the roles and mechanisms of lncRNA-n385229/miR-497/(IGF-1R/FGFR1）axis in regulating chemoresistance of pancreatic cancer by in vitro and in vivo experiments. We will also evaluate clinical values of lncRNA-n385229/miR-497 in predicting sensitivity to chemotherapy and prognosis of pancreatic cancer patients. This study will help us further investigate the mechanisms of chemoresistance in pancreatic cancer, and provide a new molecular target for assessing chemosensitivity and reversing drug resistance.

英文关键词： Pancreatic cancer;Chemoresistance;Long non-coding RNA;Competing endogenous RNAs;miRNA