RNF180下调JAK/STAT-3信号通路活性抑制胃癌淋巴结转移的机制研究

JAK/STAT-3通路激活对于细胞增殖和恶性转化起到极为重要作用，并与恶性肿瘤侵袭及转移密切相关。我们在前期研究发现胃癌细胞向淋巴结转移受控于STAT-3的表达水平和磷酸化程度，并发现胃癌组织中RNF180基因启动子DNA甲基化导致RNF180表达下调而促进胃癌的预后变差。RNF180含有RING结构域，属泛素连接酶E3家族，提示RNF180可能通过泛素化降解Jak/STAT-3信号分子或Jak/STAT-3信号的上游活化因子而抑制STAT-3的表达及其下游调控因子的激活，最终抑制了胃癌细胞淋巴结转移的发生。本项目将深入研究RNF180调控Jak/STAT-3信号的分子途径，以及影响胃癌细胞淋巴管转移的Jak/STAT-3信号下游效应分子，为控制胃癌转移提供新的策略。

The activation of JAK/STAT pathway, as an important role in cellular proliferation and malignant transformation, is significantly associated with invasion and metastasis of malignancies. Our previous work proved that both STAT-3 expression and phosphorylated level of STAT-3 could mediate lymph node metastasis of cancer cells, and the low level expression of ubiquitin ligase RNF180, caused by DNA methylation of RNF180, was the key role to affect the prognosis of gastric cancer. RNF180 includes the RING finger protein domain and functions as an E3 ubiquitin ligase, representing that RNF180 may be involved in the ubiquitination process of JAK/STAT-3 or its up-stream proteins in gastric cancer cells for inhibition the lymph node metastasis of cancer cell via the activation of the STAT-3 signal transduct pathway. In this study, we intend to elucidate the specific mechanism of RNF180 influence of ubiquitination process of STAT-3 hydrolysis activity, which could be used to demonstrate that the feasibility of inhibition the lymph node metastasis of gastric cancer regulated by RNF180 mediating JAK/STAT-3 ubiquitin proteolysis pathway.