IFNγ Suppresses Hepatocarcinogenesis Induced By FXR Deletion And Chemical Carcinogen

Background and Aims:Liver tumor, especially hepatocellular carcinoma (HCC), is closely associated with chronic inflammation. Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, plays key roles in bile acid, cholesterol, lipid, and glucose metabolism. We previously showed that FXR knockout (FXR-/-) mice displayed disrupted metabolism and chronic inflammation, and developed spontaneous liver tumors when they are over1year old. However, the mechanisms by which inflammation leads to HCC in the absence of FXR are unclear. IFNy is one of the most up-regulated pro-inflammatory cytokines in FXR-/-livers, however, whether it is tumor suppressor or promoter gene is still under debate. Therefore, we generated IFNγ-/-FXR-/-double knockout mice to determine IFNγ’s roles in the initiation and progression of hepatocarcinogenesis.Methods:IFNy-/-mice were crossed to FXR-/-mice with C57BL/6background. By biochemical and histological analyses of spontaneous hepatocarcinogenesis or hepatocarcinogen diethylnitrosamine (DEN)-induced hepatocarcinogenesis, we investigated IFNy’s roles in cancer initiation and progression. We also used in vitro experiments and xenograft models to study IFNy’s therapeutic roles in hepatocarcinogenesis.Results:IFNy deletion accelerated the spontaneous hepatocarcinogenesis inγ FXR-/-mice and increased the susceptibility to DEN-induced hepatocarcinogenesis, which were correlated with enhanced hepatocyte necrosis and apoptosis, inflammatory cell infiltration, and compensatory proliferation in the mouse livers. To study the initiation of tumorgenesis, we induced acute liver injury by DEN treatment and observed increased activation of HCC promoters STAT3and JNK/c-Jun, but decreased induction of p53in IFNγ-/-livers. Moreover, NF-kB and p53activities were increased in aging wild-type mice but not in aging IFNy-/-or IFNγ-/-FXR-/-mice, while sustained activation of STAT3and JNK/c-Jun was present in IFNγ-/-or IFNγ-/-FXR-/-mice in both HCC models.Conclusion:Increased IFNy expression in FXR-/-livers represents a protective response of liver against chronic injury and tumorigenesis. IFNy suppresses hepatocarcinogenesis by inducing expression p53and preventing activation STAT3and JNK/c-Jun.