类泛素化蛋白水解酶I（SENP1）调控肝细胞癌生长转移的作用和机制研究

SUMO化修饰是近年来研究较多的一种小类泛素化修饰方式。SUMO化过程是一个可逆的动态循坏过程，其逆反应过程（称作去SUMO化）依赖于SUMO特异性蛋白酶（SUMO-specific proteases，SENPs）的作用,但其在肝细胞癌发生发展中的作用和机制还不明确。我们的初步研究表明SENP1在肝癌组织中高表达，且与肝癌分期和转移相关。近年来的研究发现， SUMO化修饰可能是调控HIF-1α稳定性及转录活性的重要方式。本课题一方面要结合临床数据和功能研究，确定SENP1参与肝癌发生发展的作用和机制，另一方面拟从两个层面揭示SENP1调控肝癌细胞生物学特性的分子机制：一是阐明SENP1调控的HIFα去SUMO化在肝癌发生发展中作用和机制，二是利用SILAC技术鉴定SENP1直接靶向的SUMO化蛋白，进而为寻找和发现可用于肝癌治疗的靶点或药物提供线索或基础。

Hepatocellular carcinoma, HCC is a major malignancy worldwide and the second commonest fatal cancer in China. Despite definite improvements in the outcome of patients with HCC, the overall prognosis of this cancer is still unsatisfactory because of late presentation and frequent tumor recurrence after surgical resection. New adjuvant treatment modalities for HCC are much awaited. In this regard, knowledge of the molecular and cellular targets underlying the development and progression of HCC is of importance as this can provide novel opportunities for therapeutic interventions for this cancer. The molecular mechanisms of HCC are however unclear. Post-translational protein modifications by members of the ubiquitin family are widely recognized as important regulatory control systems for a variety of biological pathways. Post-translational modification of proteins involves conjugation by members of the small ubiquitin-related modifier (SUMO)/sentrin family. SUMO chains facilitate the recruitment of ubiquitin ligases, which subsequently target poly-ubiquitinated and/or poly-SUMOylated proteins for proteasomal degradation. SUMO conjugation (SUMOylation) is a dynamic process in that it can be readily reversed by a family of Sentrin/SUMO-specific proteases (SENPs) (de-SUMOylation. Six SENP proteins (SENP1, SENP2, SENP3, SENP5, SENP6, and SENP7) have been identified in human. Each of these SENPs has distinct subcellular localization and substrate specificity, suggesting that they are non-redundant. SENP1 is essential for stabilization of HIF1α during hypoxia. Hypoxia is frequently found in HCC due to the rapid growing nature of HCC. Cells adapt to hypoxia through hypoxia-inducible factors (HIFs) which are composed of the constitutively expressed HIF-1β subunit and the oxygen sensitive subunit HIF-1/2α. .In this proposal, we hypothesize that SENP1 plays an important role in hepatocarcinogenesis by regulating HIFs via deSUMOylation, particularly in a hypoxic tumor microenvironment commonly seen in HCC. We propose to 1) evaluate the expression and clinical significance of SENP1 in HCC; 2) characterize the functional role of SENP1 in HCC; and 3) delineate the molecular mechanism by which SENP1 works in HCC.