UCH37/Rpn13通过泛素蛋白酶体途径调控NCOA1参与肝癌发生的分子机制

Ubiquitin-proteasome pathway (UPP) plays an important role in the cellular biological function through regulation of protein degradation and dynamic balance of protein substrates between ubiquitination and deubiquitination. Our previous studies have shown that express level of ubiquitin carboxyl-terminal hydrolase 37 (UCH37) and nuclear receptor coactivator 1 (NCOA1) were relatively higher in hepatocellular carcinoma than those in normal liver tissue. The interaction between UCH37 and NCOA1 was also confirmed. UCH37 may cooperate with 26S proteasome complex ubiquitin receptor, subunit Rpn13 to mediate the protein level of NCOA1 through deubiquitination. Based on our experimental results and previous reports in the literature, we hypothesized that overexpression of UCH37 could induce deubiquitination of the substrate protein NCOA1 and increases its accumulation through their interaction. NCOA1 then active downstream signal pathway to give rise to cell cycle disorders and abnormal cell proliferation and metabolism, thus resulting to the development of liver cancer. This project will detect the levels of UCH37, Rpn13 and NCOA1 in HCC, assess their clinical significance, validate the role of UCH37 and NCOA1 in development of HCC and further clarify their interactions of UCH37, Rpn13 and NCOA1 and the molecular mechanism of UCH37 and Rpn13-induced NCOA1 deubiquitination in tumorigenesis of HCC to provide a theoretical basis for liver cancer diagnosis and treatment.

泛素蛋白酶体途径（UPP）通过调控底物蛋白泛素化/去泛素化动态平衡，参与细胞多种生物学功能。我们前期研究表明：泛素羧基末端水解酶UCH37和核受体共活化因子NCOA1在人肝癌中过量表达，并初步证实UCH37与NCOA1存在相互作用，UCH37与26S蛋白酶体泛素受体Rpn13可能协同通过去泛素化途径调控NCOA1的蛋白含量。根据以往实验基础和相关文献报道，本项目拟探讨UCH37、Rpn13和NCOA1在人肝癌中的表达相关性及其临床意义；利用体内、外实验，验证UCH37、Rpn13和NCOA1在肝癌发生中的作用；明确UCH37、Rpn13和NCOA1三者的相互作用，阐明UCH37通过与Rpn13协同作用，与NCOA1形成三元复合物，通过UPP诱导NCOA1去泛素化增加而聚积，激活下游信号通路，使细胞增殖增多、代谢异常，从而导致肝癌发生的分子机制，为肝癌早期诊断和个体化治疗提供依据。

泛素—蛋白酶体途径是Hershko等在二十世纪末发现的一种高效蛋白质降解途径，该途径通过蛋白酶体高效、高度选择性地进行蛋白质泛素化降解，破坏损伤陈旧的或合成过程中错误折叠的蛋白质，参与和调控多种细胞生物学过程，对维持细胞的正常生理功能具有十分重要的意义。泛素蛋白酶体途径（UPP）通过调控底物蛋白泛素化/去泛素化动态平衡，参与细胞多种生物学功能。我们研究表明：泛素羧基末端水解酶UCH37和核受体共活化因子NCOA1在人肝癌中过量表达，并初步证实UCH37与NCOA1存在相互作用，UCH37与26S蛋白酶体泛素受体Rpn13可能协同通过去泛素化途径调控NCOA1的蛋白含量。本项目探讨了UCH37、Rpn13和NCOA1在人肝癌中的表达相关性及其临床意义；利用体内、外实验，验证了UCH37、Rpn13和NCOA1在肝癌发生中的作用；明确了UCH37、Rpn13和NCOA1三者的相互作用，阐明了UCH37通过与Rpn13协同作用，与NCOA1形成三元复合物，通过UPP诱导NCOA1去泛素化增加而聚积，激活下游信号通路，使细胞增殖增多、凋亡减少，从而导致肝癌发生的分子机制，为肝癌早期诊断和个体化治疗提供了理论依据和实践基础。