低氧是肿瘤生存的重要微环境之一，它主要通过低氧诱导因子(HIFs)实现对肿瘤发生发展的调控。最近，我们的研究发现低氧微环境通过稳定HIF-2alpha蛋白，增加Sirtuin家族中的一个成员Sirt6的泛素化水平，进而促进Sirt6蛋白的降解。本课题拟在此基础上，通过我们已经建立的双荧光蛋白报告基因分析系统发现HIF-2alpha调控的，并诱导低氧下Sirt6降解的泛素E3连接酶或去泛素化酶，并进一步研究HIF-2alpha调控该酶表达和诱导Sirt6蛋白降解的分子机制及其在肝癌发生发展中的作用。这些研究工作将对认识低氧调控肿瘤发生发展的分子机制，尤其是HIF-2alpha和Sirt6及其翻译后修饰的功能具有重要价值，也可能为肝癌的治疗提供潜在的新靶点。

Hypoxia is an important micro-environment of tumor growth. It is mainly regulated by hypoxia inducible factors (HIFs) to control the development of tumor. Recently, our study found that hypoxia can increase Sirt6 ubiquitination level through HIF-2alpha to inhibit the Sirt6 protein expression. On this basis, we intend to detect the Sirt6 ubiquitin E3 ligase or its deubiquitin enzyme under hypoxia condition by dual fluorescent protein reporter assay system, and further study the effect of HIF-2alpha down-regulates the expression of Sirt6 and its function in hepatocellular carcinoma. This work will provide important clues to know how hypoxia regulates cacinogenesis and tumor development, especially the function of HIF-2alpha and the post translation modification of Sirt6. It also may provide potential new targets for the hepatocellular carcinoma treatment.