Nrf2依赖的XRCC5/hTERT信号轴在肝细胞癌转移中的功能、机制和临床意义研究

作为端粒酶的催化亚基, hTERT已被证实在大多数肿瘤中高表达并促进肿瘤的生长和转移，但其在肿瘤中高表达的机制仍不明确。前期我们在肝细胞癌（HCC）细胞中鉴定出新的与hTERT启动子结合的蛋白XRCC5，该蛋白在HCC细胞中高表达、并上调hTERT表达和促进细胞迁移和侵袭。进一步研究发现Nrf2是XRCC5相互作用蛋白，沉默Nrf2后，XRCC5对hTERT的上调则不明显。提示XRCC5对hTERT调控作用很可能依赖于Nrf2的相互作用。本项目拟通过体外和体内实验进一步研究Nrf2与XRCC5相互作用的机制、完善XRCC5对hTERT的调控机制和生物学功能。同时，收集HCC患者标本和临床资料，探讨XRCC5/Nrf2/hTERT信号轴与HCC患者转移及预后的关系。本项目的完成，将阐明新的XRCC5与Nrf2相互作用调控hTERT在HCC转移中的机制和临床意义，可能为HCC的诊治提供新策略。

As the catalytic subunit of telomerase, human telomerase reverse transcriptase (hTERT) is highly expressed and important for cancer growth and metastasis in most tumors. However, the molecular mechanism for its high expression remains unclear. In our preliminary study, we identified XRCC5 as a novel hTERT promoter-binding protein in hepatocellular carcinoma (HCC) cells. We found that XRCC5 was highly expressed in HCC cells, enhanced hTERT expression and promoted HCC cells migration and invasion. Further study showed that Nrf2 interacted with XRCC5, and hTERT up-regulation by XRCC5 was insignificant when Nrf2 was knocked down. Our results suggested that the XRCC5-regulated hTERT expression possibly depended on the interaction between XRCC5 and Nrf2. In this study, we will explore the molecular mechanisms by which Nrf2 interacts with XRCC5, and the mechanisms by which XRCC5 regulates hTERT expression in vivo and in vitro, so as to reveal the biological functions of XRCC5 in HCC. Moreover, we will collect HCC tissue specimens together with clinical information to evaluate the relationship between the XRCC5/Nrf2/hTERT signaling axis and HCC metastasis and prognosis. Our study will illuminate new mechanisms and clinical significance of the XRCC5/Nrf2/hTERT signaling axis in HCC metastasis, which may provide a new strategy for the diagnosis and treatment of HCC.