P2-HNF4α促进肝癌细胞增殖的分子机制

肝细胞癌恶性度高，预后差，其发生发展机制尚未明了。已有研究表明P1启动的HNF4α（P1）在抑制肿瘤细胞增殖中有重要作用。我们前期观察到P2启动的HNF4α（P2）在肝癌细胞中高表达，且与P1表达负相关，并受启动子甲基化修饰调控；统计分析提示P2表达与肝癌分化程度及预后相关；实验表明沉默P2表达抑制肝癌细胞增殖。因此，我们提出P2与P1功能不同，并促进肝癌细胞增殖的假说。本项目拟采用一系列分子细胞生物学及免疫学实验技术，利用过表达或敲除P2的细胞和动物模型，在蛋白表达调控及细胞功能上，明确P2在肝癌中的表达及其临床意义，揭示P2在肝癌中高表达的调控机制，寻找P2促进细胞增殖的作用通路，探讨P2在肝癌细胞生长中的作用及其分子机制，并阐明P2在肝癌细胞分化中的作用，从而获得P2参与肝癌细胞增殖和分化的可靠证据，为诠释肝癌发生发展的分子机制和寻找肝癌治疗新靶点提供充分的科学依据。

Hepatocellular carcinoma (HCC), with high morbidity and mortality, is one of the most prevalent malignancies worldwide. However, the nature of HCC progression remains elusive. It has been demonstrated that P1 promoter-driven HNF4α (P1) plays an important role in HCC cell proliferation. Recently, we found that expression of P2 promoter-driven HNF4α (P2) was increased in HCC, and inversely associated with P1 expression. P2 expression seemed to be modulated by promoter methylation. Statistical analysis revealed that P2 expression was correlated with tumor differentiation and prognosis. Following study showed that knockdown of P2 expression inhibited HCC cell viabilities. Based on our findings, we assume that P2 functions differently from P1, and promotes cell proliferation in HCC. In this study, we aim, in vitro and in vivo, to determine P2 expression and its clinical significance in HCC, to disclose the regulation of P2 expression, to quest for the pathway via which P2 promotes cell proliferation, to reveal the mechanism through which P2 is involved in tumor growth and differentiation, using a series of biological and immunological experiments in cell and animal models. Our study is likely to provide not only solid evidence that P2 is capable of facilitating cell proliferation and differentiation, but also promising therapeutic target in HCC treatment.