原发性肝癌男女发病率之比达到3-6:1。探讨肝癌发生性别差异的机制，对于肝癌针对性预防和治疗具有重要意义。前期我们应用基因敲除动物模型等，证实PDGFRα活化是β-catenin缺失或抑制条件下肝癌发生的重要原因；而PDGFRα活化在男性/雄性肝癌中占明显优势。通过筛选，我们发现PDGFRα3'-UTR存在Y染色体性别决定基因SRY结合位点。预实验证实，肝癌中SRY与PDGFRα表达水平一致；且抑制SRY可显著降低PDGFRα表达；SRY在约85%男性肝癌中高表达。由此推测：SRY可能是男性/雄性肝癌发生的重要机制之一，亦可能是肝癌发生性别差异的重要原因。本课题拟构建肝脏特异性SRY转基因小鼠模型，通过雄性小鼠过表达SRY及雌性小鼠获得性表达SRY，分别与野生鼠比较及性别间比较，肝癌发生率的差异；结合体外实验，探讨SRY通过PDGFRα等下游分子作用的机制及SRY作为靶点治疗肝癌的可行性。

The incidence of hepatocellular carcinoma (HCC) in men is 3 to 6 times higher than women worldwide. Thus, investigating the mechanism of gender disparity of HCC occurrence might be important to specific prevention and treatment of the disease. Previously, we untilized conditional hepatic β-catenin knockout mice model, in vitro gene knockdown model and human liver cancer specimen, and proved PDGFRα upregulation might be an "escape pathway" in β-catenin knockout or inhibited mice model or HCC cell lines in hepatocarcinogenesis. And, PDGFRα upregulation was predominantly identified in male.By screening, Sex-determining region on Y chromosome (SRY) was idenfied binding site in PDGFRα 3'-UTR. The prelimary data showed SRY was also significantly upregulated in tumor of β-catenin knockout male mice, which was consistent with PDGFRα upregulation. And inhibition of SRY by Dax-1 could significantly downregulate expression of PDGFRα. SRY was further identified overexpressed in around 85% male HCC. Since β-catenin was proved to bind with SRY directly and both of them could suppress each other. Therefore, we deduced that SRY might be an vital factor for enhancement of PDGFRα expression in context of β-catenin knockout or inhibition. And moreover, SRY might be an important motivator in hepatocarcinogenesis in male, which might account for gender disparity of HCC. In this project, 1)we would firstly construct liver-specific SRY transgenic mice model line. 2) By overexpression of SRY in male mice and ectopic expression of SRY in female mice, we explore the tumor incidence under DEN induction compared with their wildtype mice; 3) Together with in vitro studies, we further investigate the potential downstream effectors, such as PDGFRα, which SRY might modulate in hepatocarcinogenesis;4) Finally, we would try to test potential effects in inhibiting HCC initiation and development by targeting SRY or PDGFRα.