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

Abstract

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 (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 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.

PRMT1 Promoted HCC Growth and Metastasis In Vitro and In Vivo via Activating the STAT3 Signalling Pathway

“…In experiments investigating the underlying mechanism, PRMT1 accelerated HCC through the STAT3 pathway at the mRNA and protein levels. We also found that upregulating PRMT1 can increase STAT3 phosphorylation and thereby activate the STAT3 pathway, which can potentiate the development of HCC [22][23][24][25][26][27]. Finally, cryptotanshinone, a STAT3 inhibitor, suppressed HCC growth and migration through inhibiting STAT3 phosphorylation, which was activated by PRMT1 overexpression.…”

Tumor Suppressor Down-Regulation Promotes Hepatocyte Proliferation: A New GANKster on the Block

“…In conjunction with a recent report showing that knockout of gankyrin suppressed HCC growth, 5 this study provided further insight into a potential molecular target for treating HCC by modulating tumor cell growth and proliferation. In addition, findings correlating gankyrin overexpression with poorer survival and advanced cancer stage render it an appealing and potentially novel prognostic tumor biomarker 6 .…”

Liver Proliferation Is an Essential Driver of Fibrosis in Mouse Models of Nonalcoholic Fatty Liver Disease

“…In the course of these studies, we found that cyclin D3–cdk4 phosphorylates C/EBPα at Ser193 and increases formation of C/EBPα‐p300 complexes, which in turn activate enzymes of TG synthesis and cause hepatic steatosis . In addition to cdk4, several recent papers provide evidence that a number of strong initiators of liver proliferation and oncogenes are elevated in human liver biopsies from patients with NAFLD and in animal models of NAFLD at early stages of the disease . Previous studies suggested that hepatic steatosis causes further steps of NAFLD.…”

“…In agreement, it has recently been shown that some strong initiators of liver proliferation and oncogenes are elevated in human liver biopsies from patients and in animal models with NAFLD. These proliferative markers include the elevation of gankyrin (Gank), cyclin‐dependent kinase 4 (cdk4), and cyclin D3 and activation of the E2F1 pathway . Several recent reports showed that inhibition of cdk4 prevented and reversed the NAFLD phenotype .…”

“…It has been shown that the Gank transgenic zebrafish model spontaneously develops hepatic steatosis, fibrosis, and hepatocellular carcinoma (HCC) . Gank is elevated in mice with HFD‐mediated NASH and in patients with NASH . One downstream target of Gank is the RNA‐binding protein CUG repeat binding protein 1 (CUGBP1).…”