胆汁酸核受体FXR在肝癌中的作用和分子机制研究

项目名称： 胆汁酸核受体FXR在肝癌中的作用和分子机制研究

项目编号： No.81472232

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 陈卫东

作者单位： 河南大学

项目金额： 78万元

中文摘要： 阐明肝癌的分子机制有助于新药开发，挽救肝癌患者的生命。我们已发表的工作表明，胆汁酸核受体FXR是关键的炎症抑制子，它能够通过拮抗NF-κB信号通路抑制炎症。我们和其他研究组发现15个月以上的FXR基因敲除小鼠可发生自发性肝癌。在预实验中，我们发现FXR激活可以抑制HepG2肝癌细胞的增殖和JNK信号通路。这些结果表明FXR在肝癌中起重要作用，可能是肝癌的抑制子。在本课题中我们将考察FXR抑制JNK信号通路和抑制肝癌细胞增殖的作用和分子机制。此外，在本课题中我们还将鉴定肝脏肿瘤病变过程中FXR调控失衡的内在分子机制：具体是鉴定内源性FXR配体各成份在个体病变过程中的变化情况，以及FXR在正常肝细胞中高表达和肝癌细胞中低表达的转化分子机制。该项目内容均属首次阐述，集中揭示FXR在肝癌中的作用和机制，所得结果有助于鉴定FXR是否是潜在的治疗肝癌的药物靶向，并对其它器官癌症的治疗具有潜在指导意义。

中文关键词： C09_肝和肝内胆管肿瘤；胆汁酸；核受体FXR；JNK信号通路；增殖

英文摘要： Elucidating the mechanisms of liver tumorigenesis could lead to life-saving therapy for a large number of patients with liver cancer. Our publication has shown that bile acid nuclear receptor Farnesoid X receptor (FXR) negatively regulates hepatic inflammatory response through antagonizing NF-κB signaling pathway, which indicates that FXR is a key negative regulator in chronic inflammation. We and Gonzalez's group found that FXR knockout mice after 15 months of age spontaneously develope liver tumors. Most recently, our preliminary data show that FXR activation is able to suppress proliferation of human liver cancer HepG2 cells. Furthermore, our preliminary data show that FXR activation significantly inhibits c-Jun N-terminal kinase (JNK) activity in vitro and in vivo. These results indicate that FXR plays a critical role in liver tumour development as a negative regulator of carcinogenesis. Sustained JNK activity is often found in liver tumor, and inhibition of JNK leads to antitumor activity in liver cancer. Therefore, to better understand the molecular mechanisms by which FXR suppresses liver cancer, we will focus on the potential relationship between FXR and JNK signaling pathway in this proposal. In Specific Aim 1 of this proposal, we will determine whether FXR antagonizes JNK signaling pathway in liver carcinogenesis by activating superoxide dismutase 3 (SOD3) transcription and then suppressing the production of reactivate oxygen species (ROS). In Specific Aim 2, we propose to identify the levels of endogenous FXR ligands such as bile acids, oxysterols and others, at different stages of liver cancer. In this specific aim, we will reveal the molecular mechanisms by which FXR expression is decreased during liver tumour development. These results from this proposal will help us determine whether FXR is a potential therapeutic candidate for prevention and treatment of liver cancer, which may also have potential implications for treatment of many other types of cancer.

英文关键词： liver tumourgenesis;bile acids;nuclear receptor FXR;JNK signaling pathway;proliferation