HBP1对AFP的转录调控机制及其在肝细胞癌发生发展中的作用

肝细胞癌是肝脏常见的恶性肿瘤之一，在我国发病率很高。甲胎蛋白（AFP）异常高表达与肝细胞癌的发生发展密切相关，但AFP基因的转录调控机制以及在肝细胞癌时特异激活的分子机制尚不清楚。我们的研究初步证实转录因子HBP1转录抑制AFP基因的表达，通过下调AFP蛋白水平，降低AFP对PTEN，Caspase-3等蛋白的抑制作用，从而抑制肝癌细胞的恶性表型。如果HBP1 knockdown，则促进AFP基因表达，促进肝癌细胞的恶性表型。动物实验也证实HBP1敲除小鼠易诱导肝细胞癌的发生，提示HBP1缺失或突变可能是AFP基因转录激活并诱发肝细胞癌的重要因素。本项目拟深入探讨HBP1转录调控AFP基因表达的分子机制，揭示HBP1-AFP信号通路调控肝癌细胞增殖和侵袭的作用机制，以及这条信号通路在肝细胞癌发生发展中的作用，为肝细胞癌的预防、治疗，以及药物靶点的筛选提供理论与实验依据。

Hepatocellular carcinoma (HCC) is one of the common malignent liver tumors and its morbidity is high in our country. The abnormal high expression of alpha-fetoprotein (AFP) is intimately associated with HCC progress, but the mechanism of transcriptional regulation and singularly activation of AFP gene in HCC genesis and development is not clear. Our study tentatively demonstrated that transcription factor HBP1 represses the expression of AFP gene. HBP1 inhibits HCC cells malignancy through decreasing AFP protein level, thus attenuating the inhibition of AFP to the target proteins of PTEN，Caspase-3. HBP1 knockdown by shRNA promotes AFP expression and HCC cells malignancy. The animal experiment indicated that HBP1 knockout is easy to induce HCC in mice. Our data suggests that HBP1 deletion or mutation may be an important reason to activate AFP gene expression and induce HCC. In this study, we will explore thoroughly the mechanisms of HBP1 regulating AFP gene expression and HBP1-AFP signal pathway impacts on growth and invasion in HCC cells, as well as the role of HBP1-AFP signal pathway in HCC genesis and development. The investigation will provide theorial and experimental basis for preventing, healing and screening the drug target for HCC.