RACK1与Nanog相互作用参与肝细胞癌干细胞自我更新的分子机制研究

项目名称： RACK1与Nanog相互作用参与肝细胞癌干细胞自我更新的分子机制研究

项目编号： No.81472736

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： 张纪岩

作者单位： 中国人民解放军军事科学院军事医学研究院

项目金额： 74万元

中文摘要： 肿瘤干细胞学说是人类认识肿瘤的里程碑式进展，为治愈肝癌提供了契机。肝细胞癌(HCC)是最常见的肝癌，最近，维持胚胎干细胞多能性和自我更新的转录因子Nanog在HCC干细胞中的核心作用已得到揭示，但Nanog在这群细胞中高水平表达和维持干性特征的机制还很不清楚。我们发现WD40家族重要成员RACK1在HCC细胞中高表达、促进HCC细胞恶性生长。更重要的是，RACK1是干性维持的关键分子，与Nanog直接结合并增强Nanog蛋白的稳定性 (Hepatology 2013和待发表数据)。本项目将分析RACK1对Nanog翻译后修饰和活性的影响与机制，揭示对Nanog的调控作用是否为RACK1参与干性维持的关键机制，探讨Nanog是否也通过RACK1促进干性，我们的结果可望为肿瘤干细胞调控机制的研究取得理论上的突破，并为发展新型干预治疗措施提供线索。

中文关键词： C09_肝和肝内胆管肿瘤；肿瘤干细胞；Nanog；RACK1；相互作用

英文摘要： The cancer stem cell model, a milestone in cancer biology, provides clues to cure liver cancer. Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Recently, it has been revealed that Nanog, a transcription factor essential for the pluripotency and self-renewal of ES cells, plays a central role in the maintenance of the stemness of HCC stem cells. However, the molecular mechanisms underlying Nanog overexpression in HCC stem cells and the molecular mechanisms by which Nanog contributes to the stemness of these cells remain elusive. We have disclosed that RACK1, an important member of WD40 family, exhibits elevated expression in HCC cells and augments in vitro HCC cell proliferation and resistance to TRAIL- or Fas-mediated apoptosis as well as in vivo tumor growth. More importantly, RACK1 promotes the stemness of HCC stem cells, directly binds to Nanog, and augments the stability of Nanog (Hepatology 2013 and unpublished data). This project aims to elucidate the roles of RACK1 in modulating the post-translational modification as well as the transcriptional activity of Nanog and the underlying mechanisms, to analyze whether RACK1 promotes the stemness of HCC stem cells mainly through Nanog, to explore whether Nanog also contributes to the stemness of these cells partially through RACK1. The corresponding findings might reveal an important mechanism underlying the generation and self-renewal of HCC stem cells and provide novel strategies and potential drugs for the treatment of liver cancer.

英文关键词： liver cancer;cancer stem cells;Nanog;RACK1;interaction