长链非编码RNA GAS5调控基因翻译的分子机制及其在膀胱癌发展中的作用

项目名称： 长链非编码RNA GAS5调控基因翻译的分子机制及其在膀胱癌发展中的作用

项目编号： No.81502203

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： 陈蔚

作者单位： 南京大学

项目金额： 18万元

中文摘要： 膀胱癌是最常见的泌尿系统恶性肿瘤。由于发病机制不甚清楚，我们迫切需要揭示膀胱肿瘤发生发展的分子机制。长链非编码RNA Growth arrest-specific 5（GAS5）能够调控细胞的生存和死亡，近年来研究发现它在多种肿瘤中表达降低，但机制研究不多。我们发现GAS5的表达与临床膀胱癌的恶性程度相关。细胞质中的GAS5与真核翻译起始因子eIF4E结合，且该相互作用在膀胱癌细胞中明显减弱。eIF4E能参与GCN2压力感受信号介导的选择性翻译抑制。由此我们提出存在GAS5选择性调控基因翻译的分子机制，直接影响膀胱癌的发展。本课题将扩大临床膀胱癌样本的检测，并建立细胞模型研究GAS5在膀胱癌中的功能；通过免疫共沉淀技术，确定GAS5相互作用的蛋白并筛选其调控的关键效应mRNA。本研究将阐述GAS5如何通过翻译调控影响膀胱癌发展，为临床治疗研究提供更多靶点和数据基础。

中文关键词： 膀胱癌；长链非编码RNA；GAS5；翻译调控

英文摘要： Bladder cancer is the most common malignant tumor of urinary system. Because of unknown pathogenesis, there is an urgent need for revealing the molecular mechanisms of the initiation and development of bladder cancer . Growth arrest-specific 5 (GAS5) is a long non-coding RNA with the function of regulation cell survival. Recently, the expression of GAS5 has been proved significantly decreased in tumors, however, the precise signaling pathway remains largely unknown. In present study, we found that GAS5 levels were highly related with the pathology grade and TNM stage of bladder cancer. We found that the GAS5 can interact with eukaryotic translation initiation factor eIF4E, participating in the control of gene translation. Moreover, the interaction between GAS5 and eIF4E is much weaker in bladder cancer cell line. The eIF4E was also found to be partly involved in selective translational control mediated by GCN2 signaling. Hence, it is important to understand the translational control mechanisms of GAS5 for the development of bladder cancer. In this project, we will expand the bladder cancer samples to determine the clinical significance of GAS5. We will also establish cell models to study the function of GAS5 in bladder carcinoma development. Then, we will screen the important interaction proteins and key effector mRNAs of GAS5, through specific RNA pull down and RNA binding protein immunoprecipitation techniques. This research will elucidate the specific translational control by GAS5 in the development of bladder cancer, and provide more potential targets and ample basis for clinical therapy of bladder cancer.

英文关键词： bladder cancer;long non-coding RNA;Growth arrest-specific 5 （GAS5）;translational regulation