FXR调控JAK2/STAT3信号通路抑制肝癌形成的分子机制研究

FXR是肝脏中重要的转录调控因子，具有抑制肝癌形成的功能，但其抑制肝癌发生、发展的分子机制至今仍未完全阐明。我们的前期研究首次发现，FXR基因敲除小鼠早期肝脏中JAK2/STAT3炎性分子通路即被激活。本研究的目的是：明确FXR通过抑制JAK2/STAT3信号通路活化来阻滞肝癌发生、发展的作用，并阐明 FXR调控肝脏JAK2/STAT3信号通路的分子机制。因此，本课题拟应用FXR基因敲除小鼠肝癌模型，证明肝癌发生、发展过程中FXR对JAK2/STAT3通路的调控作用；并进一步通过FXR基因敲除小鼠、染色质免疫沉淀、分子克隆、荧光素酶报告等实验手段阐明FXR对JAK2/STAT3信号通路调控的分子机制。本研究将开拓人们对FXR抑制肝癌发生、发展分子机制的认识，并为以FXR及JAK2/STAT3分子通路为靶点预防和治疗肝癌提供新的理论依据和实验基础。

Farnesoid X Receptor(FXR) is one of the most important transcription factor in the liver. FXR can suppress liver carcinogenesis, however the underlying molecular mechanisms are still not known. Our preliminary data showed that JAK2/STAT3 inflammation pathway was activated at early age in livers of FXR-Knockout mice. Thus, the current research aims to demonstrate FXR in inhibition of liver carcinogenesis through JAK2/STAT3 signaling pathway, and to elucidate the underlying molecular mechanisms of FXR in regulation of JAK2/STAT3 signaling pathway. Hepatocellular carcinoma(HCC) model in FXR-Knockout mice will be used to elucidate the functions of FXR in regulation of JAK2/STAT3 signaling pathway in the liver. Moreover, FXR-Knockout mouse models, chromatin immunoprecipitation(ChIP) assay, molecular cloning, luciferase assay and other cellular biology and molecular biology experiments will be used to demonstrate the underlying molecular mechanisms of FXR in regulation of JAK2/STAT3 signaling pathway in the liver. These researches will develop the understanding of FXR in suppression of HCC initiation and progression. Furthermore, the current project will provide new theoretical foundation and experimental basis for prevention and treatment of HCC through FXR and JAK2/STAT3 signaling pathway.