RNF43介导的AKT/MDM2和NEDL1途径调控肝癌细胞恶性行为的分子机制

项目名称： RNF43介导的AKT/MDM2和NEDL1途径调控肝癌细胞恶性行为的分子机制

项目编号： No.81502012

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： 邢春阳

作者单位： 浙江大学

项目金额： 18万元

中文摘要： 寻找新的生物治疗靶标对提高肝癌的疗效具有重要意义，我们前期通过Oncomine数据库筛选获得的RNF43具有明显增强肝癌细胞的增殖、抗凋亡、侵袭、成瘤和血管新生能力，RNF43 表达沉默可致肝癌细胞内p53表达量的增加，RNF43 干扰前后的表达谱芯片生物信息分析发现p53途径是RNF43调控网络的中心环节。本研究拟在RNF43诱导表达状态下，通过化学抑制剂及siRNA技术特异性阻断AKT 和NEDL1，阐明AKT/MDM2和NEDL1途径在RNF43调控p53表达及肝癌细胞恶性生物学行为中的作用；观察p53抑制状态下RNF43表达变化对肝癌细胞功能的影响；进一步利用大样本肝癌临床标本，验证RNF43与p53通路相关蛋白的表达或活化水平的内在联系，揭示RNF43经p53途径对肝癌细胞功能调控作用的分子机制，为寻找新型的肝癌分子治疗靶点提供理论基础。

中文关键词： 肝细胞癌；环指蛋白43；p53；肿瘤发生；细胞增殖

英文摘要： Finding new therapeutic targets for HCC have great significance. Our previous results have demonstrated that RNF43 dramaticaly promoted tumor proliferation, anti-apoptosis, invasion, tumor formation and angiogenesis. We also found that the expression of p53 was inhibited after knocking down the expression of RNF43. Functional-network analysis of differentially expressed genes after RNF43 knockdown indicated that p53 was located at the central node of RNF43 regulatory network. Based on these findings, We will further evaluate the effects of p53 inhibiting on cell proliferation and invasion by blocking AKT and NEDL1 pathways at RNF43-overexpressed status. In addition,we will detect the effects of RNF43 on tumor malignant behavior at p53 inhibition status. Moreover, we attempt to analyze the correlation between RNF43 expression level and p53 pathway proteins in clinical HCC samples, thereby uncovering the molecular mechanisms of RNF43 on HCC regulation through p53 pathway, thus facilitate exploring a novel therapeutic target for HCC.

英文关键词： hepatocellular carcinoma;RNF43;p53;tumorigenesis;cell proliferation