Published online Oct 7, 2017. doi: 10.3748/wjg.v23.i37.6833
Peer-review started: January 20, 2017
First decision: March 16, 2017
Revised: August 24, 2017
Accepted: September 6, 2017
Article in press: September 5, 2017
Published online: October 7, 2017
To elucidate the role of STAT3 in hepatocarcinogenesis and biliary ductular proliferation following chronic liver injury.
We investigated thioacetamide (TAA)-induced liver injury, compensatory hepatocyte proliferation, and hepatocellular carcinoma (HCC) development in hepatic STAT3-deficient mice. In addition, we evaluated TAA-induced biliary ductular proliferation and analyzed the activation of sex determining region Y-box9 (SOX9) and Yes-associated protein (YAP), which regulate the transdifferentiation of hepatocytes to cholangiocytes.
Both compensatory hepatocyte proliferation and HCC formation were significantly decreased in hepatic STAT3-deficient mice as compared with control mice. STAT3 deficiency resulted in augmentation of hepatic necrosis and fibrosis. On the other hand, biliary ductular proliferation increased in hepatic STAT3-deficient livers as compared with control livers. SOX9 and YAP were upregulated in hepatic STAT3-deficient hepatocytes.
STAT3 may regulate hepatocyte proliferation as well as transdifferentiation into cholangiocytes and serve as a therapeutic target for HCC inhibition and biliary regeneration.
Core tip: Cell transdifferentiation has been identified as one of the crucial sources of organ regeneration. In liver regeneration, both mature hepatocytes and cholangiocytes have been shown to transdifferentiate to each other to maintain hepatic homeostasis. Although STAT3 has been also shown to be implicated in cellular differentiation, the differentiative role of STAT3 in liver regeneration remains unknown. In this study, we found that hepatic-STAT3 deficiency promoted biliary ductular proliferation with upregulation of Yes-associated protein (YAP)/sex determining region Y-box9 (SOX9), crucial regulators of transdifferentiation, in liver injury of mice. This work suggests that STAT3 determines liver cell fate regulating YAP/SOX9 in liver regeneration.