Research Papers:
The oncoprotein gankyrin promotes the development of colitis-associated cancer through activation of STAT3
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Abstract
Toshiharu Sakurai1, Hiroaki Higashitsuji2, Hiroshi Kashida1, Tomohiro Watanabe1, Yoriaki Komeda1, Tomoyuki Nagai1, Satoru Hagiwara1, Masayuki Kitano1, Naoshi Nishida1, Takaya Abe3, Hiroshi Kiyonari3,4, Katsuhiko Itoh2, Jun Fujita2, Masatoshi Kudo1
1Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan
2Department of Clinical Molecular Biology, Kyoto University, Kyoto, Japan
3Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe, Japan
4Animal Resource Development Unit, RIKEN Center for Life Science Technologies, Kobe, Japan
Correspondence to:
Toshiharu Sakurai, email: [email protected]
Keywords: IBD, TNF, Bmi1, IL-17, treatment resistance
Received: April 20, 2016 Accepted: December 31, 2016 Published: February 01, 2017
ABSTRACT
Although long-standing colonic inflammation due to refractory inflammatory bowel disease (IBD) promotes the development of colitis-associated cancer (CAC), the molecular mechanisms accounting for the development of CAC remains largely unknown. In this study, we investigated the role of gankyrin in the development of CAC since gankyrin is overexpressed in sporadic colorectal cancers. We analyzed gene expression of colon tissues obtained from 344 patients with IBD and CAC and found that expression of gankyrin was much higher in colonic mucosa of patients with refractory IBD than in those with IBD in remission. Expression of gankyrin was upregulated in inflammatory cells as well as tumor cells in colonic mucosa of patients with CAC. Over-expressing studies utilizing tagged ganlyrin-cDNA identified physical interaction between ganlyrin and Src homology 2-containing protein tyrosine phosphatase-1 (SHP-1). Importantly, the interaction between ganlyrin and SHP-1 leads to inhibition of STAT3 activation and to enhancement of TNF-α and IL-17 in inflammatory cells. To further address the role of gankyrin in the development of CAC, we created mice with intestinal epithelial cell-specific gankyrin ablation (Vil-Cre;Gankyrinf/f) and deletion of gankyrin in myeloid and epithelial cells (Mx1-Cre;Gankyrinf/f). Gankyrin deficiency in myeloid cells, but not in epithelial cells, reduced the activity of mitogen activated protein kinase and the expression of stem cell markers, leading to attenuated tumorigenic potential. These findings provide important insights into the pathogenesis of CAC and suggest that gankyrin is a promising target for developing therapeutic and preventive strategies against CAC.
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