胶质瘤侵袭过程中DNMT1沉默miR-134与ERK信号通路自激活的表观新机制

项目名称： 胶质瘤侵袭过程中DNMT1沉默miR-134与ERK信号通路自激活的表观新机制

项目编号： No.81502494

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： 王洪军

作者单位： 哈尔滨医科大学

项目金额： 18万元

中文摘要： 通过表观遗传学途径沉默抑癌基因的表达是癌基因信号通路的重要分子事件。前期工作对胶质瘤大样本mRNA/miRNA芯片数据分析证实：DNMT1是独立的预后因子，其表达与miR-134负相关，与ERK正相关。..本项目在对上述数据分析基础上拟开展“DNMT1经表观遗传学沉默胶质瘤中重要抑癌miRNA：miR-134，致ERK通路自激活”的表观新机制研究。首先验证DNMT1经启动子区甲基化沉默miR-134表达的调控作用及对侵袭性的影响；而后阐明miR-134经靶点K-ras反馈调控ERK，ERK经AP-1转录调控DNMT1的关系；最终在体内和体外实验水平，揭示DNMT1/miR-134/ERK环路的内在联系，以及分析对胶质瘤侵袭性生长的影响和治疗胶质瘤的疗效评估。..本研究可揭示DNMT1经表观遗传学方式沉默miR-134致ERK癌基因信号通路自激活的新机制，以期为治疗胶质瘤的新靶标提供依据。

中文关键词： 胶质瘤；非编码RNA；miR-134；侵袭；DNMT1

英文摘要： The tumor suppressor genes silencing by epigenetics plays an important role in the glioma development. The results our previous analyzed based on the mRNA/miRNA dataset in glioma showed that DNMT1 was an independent prognostic factor, negatively associated with miR-134, but positively associated with ERK.. This project aims to explore the new mechanism that DNMT1 makes the ERK self-activation by silencing miR-134, an important tumor suppressor. Firstly, we will validate the influence of DNMT1-induced miR-134 silencing on glioma cell invasion capacity. Then we will illustrate the regulation of ERK by miR-134 targeting K-ras and the feedback loop of ERK, AP-1, DNMT1.Finally, the inherent connection in the loop of DNMT1/miR-134/ERK will be revealed in the vitro cells, treated separately or together by DNMT1, ERK inhibitor and miR-134 mimics, and in the vivo model. The effect on the glioma growth and the efficacy of this treatment also will be evaluated. . Our study will reveal the new mechanism that DNMT1 makes the cancer associated signaling pathway ERK/MAPK self-activation by silencing miR-134 in glioma progression, and provide the new clue for exploring functional network system and candidate target in glioma.

英文关键词： glioma;no coding RNA;miR-134;invasion;DNMT1