Aberrantly hyperactivated STAT3 has been found in human
liver cancers as an oncogene; however, STAT3 has also been shown to exert hepatoprotective effects during liver injury. The balancing act that STAT3 plays between hepatoprotection and liver
tumorigenesis remains poorly defined. In this study, the
diethylnitrosamine (DEN)-induced liver
tumor model and the chronic
carbon tetrachloride (CCl(4))-induced
liver fibrosis model were both used to investigate the role of STAT3 in liver
tumorigenesis. Hepatocyte-specific STAT3 knockout mice were resistant to liver
tumorigenesis induced by a single DEN injection, whose
tumorigenesis was associated with minimal chronic liver
inflammation, injury, and
fibrosis. In contrast, long-term CCl(4) treatment resulted in severe hepatic oxidative damage,
inflammation, and
fibrosis but rarely induced liver
tumor formation in wild-type mice. Despite the oncogenic function of STAT3 in DEN-induced liver
tumor, hepatocyte-specific STAT3 knockout mice were more susceptible to liver
tumorigenesis after 16 weeks of CCl(4) injection, which was associated with higher levels of liver injury,
inflammation,
fibrosis, and oxidative DNA damage compared with wild-type mice. These findings suggest that the hepatoprotective feature of STAT3 prevents hepatic damage and
fibrosis under the condition of persistent inflammatory stress, consequently suppressing injury-driven liver
tumor initiation. Once liver
tumor cells have developed, STAT3 likely acts as an oncogenic factor to promote
tumor growth.