FHL在肝癌发生发展中的功能及其分子机制

项目名称： FHL在肝癌发生发展中的功能及其分子机制

项目编号： No.30870499

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 丁丽华

作者单位： 中国人民解放军军事医学科学院

项目金额： 30万元

中文摘要： 肝癌(HCC)是我国最常见的恶性肿瘤之一，但其发生发展的细胞和分子机制还未阐明。TGF-beta信号转导途径在肝脏的发育及自稳态的维持中起着重要作用，其胞内主要调控蛋白Smads表达下降及功能缺失将会导致肝癌的发生。我们利用酵母双杂交技术获得了新型的与Smads结合的蛋白FHL,并发现FHL蛋白在肝癌组织中表达降低，FHL通过与Smads蛋白相互作用促进TGF-beta下游基因的转录，预示着FHL蛋白在肝癌的发生发展过程中具有重要作用。我们将利用各种蛋白质间相互作用研究技术、报告基因检测方法、RNA干扰技术、染色质免疫沉淀、亚细胞定位分析、免疫组织化学技术、细胞生物学效应检测技术等确定FHL家族蛋白在肝癌发生发展中的作用及其分子机制以及FHL家族蛋白在肝癌细胞生长调节中的作用及其在临床上的意义，为阐明肝癌发病机理、发现新的肝癌诊断和治疗靶标打下坚实的基础。

中文关键词： 肝癌；FHL家族；TGF-beta信号通路；相互作用

英文摘要： Hepatocellular carcinoma (HCC) is one of the most malignant tumors in our country, but the molecular mechanism of its development and progression has not been elucidated. TGF-beta signaling pathway plays an important role in liver development and its homeostatic maintainance. Downregulation or dysfunction of Smads, the main cellular regulators of TGF-beta signaling pathway, will lead to HCC. Using a yeast two-hybrid, we found that FHL interacted with Smads. We also found that the expression level of FHL proteins were decreased in HCC tissue and that FHL proteins activated the transcription of downstream genes of TGF-beta signaling pathway through the interaction with Smads. These results suggest that FHL proteins play an important role in the development and progression of HCC. Using protein-protein interaction technology, reporter gene assay, RNA intereference, chromatin immunoprecipitation, subcellular localization, immunohistochemistry, and biological activity analysis, we will determine the role and molecular mechanism of FHL proteins in the development and progression of HCC, their effects on the growth regulation of HCC cell lines and their clinical significance, which will lay a strong foundation for elucidating HCC pathogenesis and finding new targets for HCC diagnosis and therapy.

英文关键词： HCC; FHL family;TGF-beta signaling;interaction