Gankyrin induces STAT3 activation in tumour microenvironment and sorafenib resistance in hepatocellular carcinoma

Abstract

Most hepatocellular carcinomas (HCCs) develop as a result of chronic liver inflammation. We have shown that the oncoprotein gankyrin is critical for inflammation-induced tumourigenesis 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 tumour 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 VEGF 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 (STAT3). Gankyrin deficiency in non-parenchymal cells, but not in parenchymal cells, reduced STAT3 activity, interleukin (IL)-6 production, and cancer stem cell marker (Bmi1 and epithelial cell adhesion molecule [EpCAM]) expression, leading to attenuated tumourigenic potential. Chronic inflammation enhances gankyrin expression in the human liver. Gankyrin expression in the tumour 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 tumour microenvironment and may be a potential target for developing therapeutic and preventive strategies against HCC.

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