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

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....

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Bibliographic Details
Published in:Cancer science 2017-10, Vol.108 (10), p.1996-2003
Main Authors: Sakurai, Toshiharu, Yada, Norihisa, Hagiwara, Satoru, Arizumi, Tadaaki, Minaga, Kosuke, Kamata, Ken, Takenaka, Mamoru, Minami, Yasunori, Watanabe, Tomohiro, Nishida, Naoshi, Kudo, Masatoshi
Format: Article
Language:English
Subjects:
Apoptosis
Biomarkers
Bone marrow
Cancer therapies
Cell adhesion & migration
Cell adhesion molecules
Clonal deletion
Colon
Colorectal cancer
Epithelial cells
Hepatitis
Hepatocellular carcinoma
Hepatocytes
Homology
Inflammation
Kinases
Laboratory animals
Liver cancer
Medical prognosis
Phosphorylation
Protein-tyrosine-phosphatase
Stat3 protein
Stem cells
Transcription
Tumor cells
Tumorigenesis
Tumors
Vascular endothelial growth factor
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Summary: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 .
ISSN:1347-9032
1349-7006
DOI:10.1111/cas.13341