VHL和ZBRK1相互作用在肾癌发生发展的分子机制

VHL 基因的缺失或突变可导致许多肿瘤，包括透明肾细胞癌。我们利用酵母双杂交技术，以 VHL 基因为诱饵发现ZBRK1 是一个新的 VHL相互作用蛋白。我们发现ZBRK1在肾癌中表达降低并且与肾癌进展及患者预后密切相关。我们通过一系列体内和体外实验证实ZBRK1在肾癌发生发展中起着抑癌基因的作用。此外，我们还发现ZBRK1通过结合到 VHL基因启动子上上调 VHL 的表达，进而抑制 VEGF 的表达。因此，我们提出假说在肾癌发展过程中，ZBRK1的低表达导致VHL/HIF通路异常，从而引起或加剧肾细胞癌的增殖、侵袭和转移。本项目拟明确VHL/ZBRK1相互作用在肾癌发生发展中的分子机制，丰富肾癌相关分子生物学理论，为肾癌治疗提供新的策略和靶点。

Inactivation or mutation of the VHL gene causes various tumors, including clear cell renal cell carcinoma (ccRCC). In our previous study, we identified ZBRK1 as an interaction protein of VHL by yeast two-hybrid screening. Our previous research indicated that ZBRK1 was significantly associated with tumor progression and prognosis. we provided evidences showing that ZBRK1 acts as a tumor suppressor in renal carcinoma by a variety of in vitro and in vivo assays. Furthermore, We found a single ZBRK1-binding site located in the VHL promoter region. Our data also showed that over-expression of ZBRK1 increased the transcription level of VHL and inhibited the VEGF transcription. So we build hypothesis that low ZBRK1 transcripts in renal cancer led to abnormality of VHL/HIF pathway, which contribute to the cell growth, invasion, and metastasis. In this project, we plan to systematically study the molecular mechanism of the interaction between VHL and ZBRK1 in renal cancer development and progression,enrich the molecular biology theory and finally contribute to the therapeutic use of VHL and ZBRK1 in RCC.