肾癌细胞中VHL失活对microRNA加工的影响

项目名称： 肾癌细胞中VHL失活对microRNA加工的影响

项目编号： No.81202010

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2

项目作者： 鲍习琛

作者单位： 中国科学院广州生物医药与健康研究院

项目金额： 23万元

中文摘要： VHL 基因失活是诱发肾癌最常见的因素之一，其失活可使HIF1/2的蛋白稳定性增强，使得肿瘤获得生长加快，周边血管生成，侵袭性增强等特征，加速肿瘤的发生和发展。microRNA对于靶基因的调控紊乱是肿瘤也是肾癌的一个重要特征，这种调控紊乱也可加速肿瘤的发生和发展。但是目前VHL失活对microRNA加工的影响尚未见报道。我们前期工作发现在VHL失活的肾癌细胞中，microRNA相关的加工蛋白（TRBP和Dicer）的表达显著下调。我们拟进一步通过microRNA实时定量PCR技术检测VHL失活对microRNA加工效率的影响。另外，我们外源过表达或者敲低TRBP和Dicer，研究它们对肾癌增殖、转移以及血管生成的影响。将肾癌中最常见的失活基因VHL和microRNA加工这两个信号通路联系起来，解释VHL失活对于肾癌发生发展的作用，甚至为肿瘤的治疗提供潜在的靶点。

中文关键词： 肾癌；非编码RNA；低氧诱导因子；体细胞重编程；维生素c

英文摘要： Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene underlies the majority of renal cell cancers (RCC), and its loss of function results in constitutive stabilization of the transcription factor HIF (hypoxia-inducible factor). HIF (HIF-1a and -2a) activates the transcription of many genes, producing cell proliferation, angiogenesis, metastasis and other alterations, which altogether causes the development of RCC. HIF also induces the expression of different microRNAs that influence tumorigenesis. Besides inducing specific sets of microRNAs, tumors in general are known to bear alterations in microRNA processing, which allows the down-regulation of key microRNAs with tumor suppression function. In this proposal we aim to investigate the effects of VHL inactivation/HIF activation on the microRNA processing of RCC cells. Our preliminary data show that VHL inactivation in RCC cells reduces the expression of the microRNA processing proteins TRBP and Dicer. Our first objective will be to study how down-regulation of TRBP/Dicer influences the efficiency of microRNA processing in VHL-defective RCC cell lines engineered to re-express wild-type or mutated forms of VHL. In addition, we will test whether down-regulation of TRBP and Dicer influences RCC cell proliferation, metastasis and angiogenesis. Moreover,

英文关键词： renal cancer；non-coding RNA；Hypoxia Induced Factor；Somatic cell reprogramming；Vitamin C