The transcription factor c-JUN/AP-1 promotes HBV-related liver tumorigenesis inmice

摘要

Hepatocellular carcinoma (HCC) develops as a consequence of chronic inflammatory liver diseases such as chronic hepatitis B virus (HBV) infection. The transcription factor c-Jun/activator protein 1 (AP-1) is strongly expressed in response to inflammatory stimuli, promotes hepatocyte survival during acute hepatitis and acts as an oncogene during chemically induced liver carcinogenesis in mice. Here, we therefore aimed to characterize the functions of c-Jun during HBV-related liver tumorigenesis. To this end, transgenic mice expressing all HBV envelope proteins (HBV⁺), an established model of HBV-related HCC, were crossed with knockout mice lacking c-Jun specifically in hepatocytes and tumorigenesis was analyzed. Hepatic expression of c-Jun was strongly induced at several time points during tumorigenesis in HBV⁺ mice, whereas expression of other AP-1 components remained unchanged. Importantly, formation of premalignant foci and tumors was strongly reduced in HBV⁺ mice lacking c-Jun. This phenotype correlated with impaired hepatocyte proliferation and increased expression of the cell cycle inhibitor p21, whereas hepatocyte survival was not affected. Progression and prognosis of HBV-related HCC correlates with the expression of thecytokine osteopontin (Opn), an established AP-1 target gene. Opn expression wasstrongly reduced in HBV⁺ livers and primary mousehepatocytes lacking c-Jun, demonstrating that c-Jun regulates hepatic Opnexpression in a cell-autonomous manner. These findings indicate that c-Jun hasimportant functions during HBV-associated tumorigenesis by promoting hepatocyteproliferation as well as progression of dysplasia. Therefore, targeting c-Jun may bea useful strategy to prevent hepatitis-associated tumorigenesis.