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

Cancer Sci. 2017 Oct;108(10):1996-2003. doi: 10.1111/cas.13341. Epub 2017 Sep 2.


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;gankyrinf/f ) and gankyrin deletion both in liver parenchymal and non-parenchymal cells (Mx1-Cre;gankyrinf/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.

Keywords: ERK; Bmi1; hepatocellular carcinoma; interleukin-6; vascular endothelial growth factor.

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Interleukin-6 / metabolism
  • Liver / metabolism
  • Liver / pathology
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Male
  • Mice
  • Niacinamide / administration & dosage
  • Niacinamide / analogs & derivatives*
  • Niacinamide / pharmacology
  • Phenylurea Compounds / administration & dosage*
  • Phenylurea Compounds / pharmacology
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • STAT3 Transcription Factor / metabolism*
  • Sorafenib
  • Survival Analysis
  • Up-Regulation
  • Vascular Endothelial Growth Factor A / metabolism


  • IL6 protein, human
  • Interleukin-6
  • PSMD10 protein, human
  • Phenylurea Compounds
  • Proto-Oncogene Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Niacinamide
  • Sorafenib
  • PTPN6 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Proteasome Endopeptidase Complex