泛素E3连接酶RLIM在肝癌发生发展过程中的作用机制研究

肝癌是我国人群最常见的癌症之一，其发病的分子机制非常复杂，也成为当下迫切的研究热点。周期相关蛋白Cyclin D1是细胞周期调控中的一个关键分子，可促进细胞从G1期向S期的转换，在多种肿瘤的恶性增殖过程中扮演重要角色。我们在前期研究中发现了一个泛素E3连接酶RLIM在肝癌中显著下调。为进一步探索其介导的分子机制。我们通过串联亲和纯化和质谱鉴定了RLIM潜在的相互作用蛋白。结果发现RLIM可以和周期相关蛋白Cyclin D1在内外源相互作用，并且可以通过泛素-蛋白酶体途径降解Cyclin D1。我们推测RLIM可以通过负调控Cyclin D1信号途径抑制肝癌细胞的恶性增殖。本课题将研究RLI的下调表达和肝癌临床指标的相关性、RLIM对Cyclin D1的泛素化修饰和降解调控、RLIM对肝癌细胞株增殖、凋亡等细胞行为的影响。并探讨其作为分子诊断标志物的可能性。

Hepatocellular carcinoma (HCC) is also one of the most prevalent malignant human cancers among adults in China. Although many susceptible signaling pathways have been implicated in HCC, the molecular basis of carcinogenesis in the liver remains largely unknown. Cyclin D1 is a key molecule in cell cycle regulation. It promotes cell from G1 phase to S phase transition and plays very important role in cancer cell proliferation. RLIM was identified as one of the potential HCC relevant genes in mRNA differential display assay. We identified Cyclin D1 as the potential RLIM interactor in a Tandem Affinity Purification (TAP) and Mass analysis. The preliminary results showed RLIM can promote Cyclin D1 ubiquitination and degradation. The aim of this project is to explore the clinico-pathological correlation of RLIM down-regulation in HCC tissues and the molecular mechanism of RLIM in Cyclin D1 regulation.