NCOA5通过调控FOXA1表达影响人肝细胞癌发生及其机制研究

肝细胞癌（HCC）与2型糖尿病（T2D）和性别有显著关联，但其中的机制仍不明确。NCOA5是独立于AF2、同时影响肝癌和T2D的共激活因子。我们的前期研究已经表明，NCOA5单倍体功能不足导致雄性小鼠发生葡萄糖耐量异常以及HCC，其中部分机制包括调控炎症分子IL-6的表达及功能。我们进一步研究发现肝癌细胞株过表达NCOA5能导致FOXA1的表达下调，而FOXA1是维持血糖动态平衡和影响肝癌发生性别差异的关键分子。因此，本项目将利用肝癌细胞、动物成瘤模型和临床标本，从细胞到整体水平进一步研究NCOA5抑制人HCC发生的作用，阐明NCOA5通过下调FOXA1表达影响肝癌发生的分子机制，同时应用高通量RNA定序分析（RNA-seq）探索NCOA5的其它下游信号分子。本研究将为HCC和T2D的关联、HCC发生的性别差异提供新的理论依据，有望为HCC的防治提供新的靶点。

Hepatocellular carcinoma(HCC) significantly correlates with type 2 diabetes and gender disparity. The underlying mechanism is not quite clear yet. NCOA5 is a coactivator independent of AF2, which influences both HCC and T2D. Previous study had showed that NCOA5 haploinsufficiancy increase glucose intolerance as well as HCC in male mice. Mechanism partially includes activate IL-6 and its function. Our further study show overexression of NCOA5 can downregulate FOXA1 expression in cells. FOXA1 is a key regulator of maintaining blood glucose of dynamic balance and gender differences of HCC. Hence, using HCC cell lines, animal tumor model and clinical specimens, this project aims to to discuss the inhibitory effect of NCOA5 in human HCC and molecular mechanisms of NCOA5 down-regulating FOXA1 expression resulting HCC. Moreover, RNA-seq was used to explore other new NCOA5 downstream signaling molecules. This project will provide new evidence for the pathogenesis of HCC and T2D, mechanisms of gender disparity in HCC , even a new target for HCC prevention and treatment.