SOX9是调控器官发育和细胞分化的重要转录因子，在多种肿瘤中表达异常。近年研究表明肝细胞在慢性损伤过程中可去分化为SOX9阳性的兼性肝干细胞，但SOX9影响肝细胞去分化的机制及其在肝癌发生中的作用尚不明确。我们既往的研究发现上调维持肝细胞分化和功能的肝细胞核因子HNF4α可预防肝癌的发生，并有效治疗多种肝癌种植瘤；近期研究发现 DEN诱导的小鼠原发性肝癌源自SOX9阳性的兼性肝干细胞，HNF4α可调控SOX9的表达，提示维持肝细胞的分化状态影响肝癌的发生。本课题拟在多种原发性肝癌小鼠模型中利用可示踪肝细胞属性转换过程的SOX9-Flp/Ai65D小鼠追踪肝癌发生的过程，明确肝细胞属性转换过程是否参与肝癌的形成；在小鼠模型中特异性敲除或过表达肝细胞SOX9表达，确定SOX9对肝癌发生的影响及相关分子通路；并揭示HNF4α通过调控SOX9抑制肝癌发生的机制，以期为肝癌防治提供新的靶点。

Sox9 is a transcription factor that plays a critical role in organ development and cell differentiation. The dysregulation of SOX9 has been reported in many cancers. Recent studies show that hepatocytes can dedifferentiate into SOX9-positive bipotential liver progenitor cells during chorionic liver injury, but the molecular mechanisms by which Sox9 regulates the dedifferentiation of hepatocyte and its role in hepatocarcinogenesis remain unclear. Hepatocyte nuclear factor 4α (HNF4α) is a transcription factor that plays a key role in hepatocyte differentiation and the maintenance of hepatic function. Our previous studies have revealed that upregulation of HNF4α blocks hepatocellular carcinoma (HCC) occurrence and exerted significant therapeutic effect on xenograft of HCC cells. Our recent experiments demonstrated that HNF4α regulates the expression of SOX9. Moreover, the lineage tracing experiment showed that the diethylnitrosamine (DEN)-induced HCC originates from SOX9-positive bipotential liver progenitor cells in mice. These data indicate that the differentiation status of hepatocytes affects hepatocarcinogenesis. In this study, we will clarify the relationship between hepatocyte dedifferentiation and hepatocarcinogenesis by using the SOX9-Flp/Ai65D transgenic mouse, a reporter mouse for hepatocyte dedifferentiation, in various primary HCC models. Moreover, hepatocyte-specific knockout or overexpression of SOX9 will be performed in mice to elucidate the effect of SOX9 on hepatocarcinogenesis and its related signaling pathways. Finally, the molecular mechanisms of HNF4α regulating SOX9 expression and its effect on prevention of HCC occurrence will be further illustrated. This study will shed new light on the molecular mechanism of hepatocarcinogenesis and provide novel targets for the prevention and treatment of HCC.