VHL表达缺失的肾透明细胞癌对蒽环类化疗药物敏感及其分子机制

项目名称： VHL表达缺失的肾透明细胞癌对蒽环类化疗药物敏感及其分子机制

项目编号： No.81472758

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王立顺

作者单位： 复旦大学

项目金额： 72万元

中文摘要： 50%以上的肾透明细胞癌（CCRCC）存在泛素连接酶VHL功能缺失，导致VHL的靶蛋白低氧诱导因子（HIF）累积，赋予肿瘤细胞生长优势和耐药特性，是肿瘤化学治疗的难点。最近，本课题组意外发现VHL表达缺失的CCRCC细胞对蒽环类药物敏感，转染VHL后对蒽环类药物敏感性反而下降；有趣的是，该效应与HIF的累积无关，提示有其它VHL下游蛋白调控肿瘤耐药性；我们利用定量蛋白质组学在全基因组范围内寻找VHL下游蛋白，并把下游蛋白用RNAi逐一沉默表达，发现VHL调控乙醛脱氢酶2（ALDH2）的表达，沉默ALDH2的表达可以显著增加CCRCC对蒽环类药物的敏感性。本项目基于这些原创性发现，深入研究VHL表达缺失的CCRCC对蒽环类药物的敏感性、VHL对ALDH2的调控以及ALDH2在药物敏感性中的作用，阐明VHL影响蒽环类药物敏感性的分子机制，为CCRCC的化学治疗提供新的治疗靶点和实验基础。

中文关键词： C12_肾；肾盂；输尿管肿瘤；VHL；蒽环类；分子机制；乙醛脱氢酶2

英文摘要： Morethan 50% of the clear cell renal cell carcinoma(CCRCC) are VHL-deficient or lose-of-function mutant, which enables the accumulation of hypoxia inducing factor（HIF） and benefits the cancer growth and enables its resistance to chemotherapy, and thus it's a problem to cinical cancer chemotherapy. Recently,different chemotherapy agents were applied to VHL-deficient cells and its counterparts with VHL, and we found anthracycline is more sensitive to VHL-deficient CCRCC. Intriguingly, this sensitivity is HIF-independent. Then quantitative proteomics were used to genome-widely discover the VHL-downstream proteins, and these dysregulated proteoins downstream VHL were knockdown with RNAi to verify which protein is invovled in the anthracycline sensitivity. Aldehyde dehydrogenase 2（ALDH2）was found to be regulated by VHL and its kockdown makes the CCRCC highly sensitive to anthracyline. This project aims to systematically investigate the high sensitivity of anthracycline to CCRCC, the expression regulation of ALDH2 by VHL and the effect of ALDH2 on the anthracycline sensitivity, revealing the molecular mechanisms for the high sensitivity of VHL-deficient CCRCC to anthracycline. This works hopefully provides new target and experimental basis for the clinical chemotherapy of renal clear cell carcinoma.

英文关键词： Clear cell renal cell carcinoma;VHL;anthracycline;molecular mechanism;ALDH2