炎症是促进肝癌发生发展的重要因素之一，但是癌基因与炎性微环境之间如何交互作用促进肿瘤进程尚不清楚。p28GANK是肝细胞癌中高表达的癌蛋白，通过调控Rb、p53、NF-κB、PI3K-AKT、β-catenin、Oct4等多条信号通路，影响肝癌前体细胞功能，细胞周期和凋亡，以及肝癌的转移。前期我们发现在爆发性肝炎病理样本、小鼠肝纤维化模型以及DEN诱导的大鼠肝硬化-肝癌模型中均存在p28GANK表达升高；而且TNFa等炎性因子可以激活p28GANK。但p28GANK在上述"质变"中的具体作用和机制尚不清楚。本课题拟借助p28GANK的转基因小鼠分别构建LPS/GalN或Jo2诱导的急性肝损伤模型、CCL4或BDL肝纤维化模型以及DEN肝癌模型，研究p28GANK在肝实质和非实质细胞中的作用及对炎性通路的影响，阐述p28GANK在肝脏炎癌转化中的作用和机制，为寻找肝病早期干预靶标奠定基础。

Hepatocellular carcinoma (HCC) is one of the most deadly human cancers. The pathogenesis of HCC is frequently linked with continous hepatocyte death, inflammatory cell infiltration and compensatory liver regeneration. Understanting the molecular mechanism driving or mediating these processes during hepatocarcinogenesis is critical for the identification of novel therapeutic targets for liver disease. p28GANK, an oncoprotein overexpressed in HCC, has been shown to expand tumor-initiating cells in hepatocarcinogenesis, disturb the balance between cell cycle and apoptosis, and promote HCC invasiveness. During these process, it engageds in entensive crosstalk with a serious of signaling pathways, including Rb,p53,NF-κB,PI3K-AKT,β-catenin and Oct4. Recently, we found that p28GANK expression increased in acute fulminant hepatitis, and progressively elevated in liver fibrosis, cirrhosis, and HCC when diethylnitrosamine (DEN)-triggered rat hepatocarcinogenesis. Moreover, Il-1βcould activate p28GANK. However, the mechanism underlying p28GANK-mediated liver fibrosis and hepatocarcinogenesis remains elusive. In this study, we will use p28GANK conditional knockout mouse to study its role in parenchymal and nonparenchymal liver cells through a series of modles, such as LPS/GalN-induced acute liver injury, bile duct ligation (BDL) or CCl4-induced liver fibrosis and DEN-mediated hepatocarcinogenesis. Although a mouse model for virally-induced hepatocarcinogenesis is still not availble, we hope above cell type-specific knockout mice models will be helpful for mechanistic understanding of p28GANK in liver diseases development from hepatitis to HCC transformation.