Open AccessGankyrin induces STAT 3 activation in tumor microenvironment and sorafenib resistance in hepatocellular carcinoma
Author(s) -
Sakurai Toshiharu,
Yada Norihisa,
Hagiwara Satoru,
Arizumi Tadaaki,
Minaga Kosuke,
Kamata Ken,
Takenaka Mamoru,
Minami Yasunori,
Watanabe Tomohiro,
Nishida Naoshi,
Kudo Masatoshi
Publication year - 2017
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13341
Subject(s) - cancer research , tumor microenvironment , sorafenib , carcinogenesis , stat protein , protein kinase b , cell growth , tumor progression , chemistry , signal transduction , biology , hepatocellular carcinoma , microbiology and biotechnology , cancer , stat3 , biochemistry , genetics , tumor cells
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 .