SHC4结合BAG2激活JAK2-STAT3通路形成正反馈环路促进肝癌进展的机制研究

肝癌是最常见的恶性肿瘤之一，JAK2-STAT3信号通路在肝癌发生发展中发挥重要作用。前期研究发现，Src同源2结构域转化蛋白4（SHC4）在促进肝癌进展中发挥重要作用并激活JAK2-STAT3通路，但其调控JAK2-STAT3通路的机制仍不清楚。进一步研究发现，SHC4通过激活JAK2-STAT3通路发挥促进肝癌进展的作用，同时能结合BAG2，BAG2可促进JAK2活化释放进而激活JAK2-STAT3通路，而STAT3参与调节SHC4在转录水平的表达。故我们提出假设，SHC4通过结合BAG2激活JAK2-STAT3信号通路，STAT3结合SHC4启动子区域促进SHC4的转录，形成正反馈环路从而促进肝癌生长和侵袭转移。本项目拟从体内、体外、临床三个水平探讨SHC4结合BAG2激活JAK2-STAT3通路形成正反馈环路的分子机制，为肝癌临床治疗提供新思路和理论依据。

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, JAK2-STAT3 signaling pathway plays an critical role in the progression of HCC. Our previous studies have found that Src Homology 2 Domain-Containing- Transforming Protein C4 (SHC4) plays an important role in promoting the progression of HCC and activating JAK2-STAT3 pathway, the mechanism by which it regulates the JAK2-STAT3 pathway remains unclear. Further studies have demonstrated that SHC4 promotes HCC progression by activating JAK2-STAT3 pathways while binding BAG2, BAG2 promotes JAK2 activation release and then activates JAK2-STAT3 pathways, STAT3 regulates the expression of SHC4 at mRNA level. Therefore, we formulate a hypothesis that SHC4 activates JAK2-STAT3 signaling pathways by binding BAG2, STAT3 binds the promoter region to enhance SHC4 transcription and forms a positive feedback loop to promote HCC growth and invasion and metastasis. This study intends to explore the molecular mechanism of SHC4 binding BAG2 to activate the JAK2-STAT3 pathway which forms a positive feedback loop in vivo, in vitro and clinically, providing new idea and theoretical basis for the clinical treatment of HCC.