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Most hepatocellular carcinomas ( HCC ) develop as a result of chronic liver inflammation. We have shown that the oncoprotein gankyrin is critical for inflammation‐induced tumorigenesis in the colon. Although the  in vitro  function of gankyrin is well known, its role  in vivo  remains to be elucidated. We investigated the effect of gankyrin in the tumor microenvironment of mice with liver parenchymal cell‐specific gankyrin ablation ( Alb‐Cre;gankyrin   f/f  ) and gankyrin deletion both in liver parenchymal and non‐parenchymal cells ( Mx1‐Cre;gankyrin   f/f  ). Gankyrin upregulates vascular endothelial growth factor expression in tumor cells. Gankyrin binds to Src homology 2 domain‐containing protein tyrosine phosphatase‐1 ( SHP ‐1), mainly expressed in liver non‐parenchymal cells, resulting in phosphorylation and activation of signal transducer and activator of transcription 3 ( STAT 3). Gankyrin deficiency in non‐parenchymal cells, but not in parenchymal cells, reduced  STAT 3 activity, interleukin ( IL )‐6 production, and cancer stem cell marker (Bmi1 and epithelial cell adhesion molecule [Ep CAM ]) expression, leading to attenuated tumorigenic potential. Chronic inflammation enhances gankyrin expression in the human liver. Gankyrin expression in the tumor microenvironment is negatively correlated with progression‐free survival in patients undergoing sorafenib treatment for  HCC . Thus, gankyrin appears to play a critical oncogenic function in tumor microenvironment and may be a potential target for developing therapeutic and preventive strategies against  HCC .

Gankyrin induces STAT 3 activation in tumor microenvironment and sorafenib resistance in hepatocellular carcinoma