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Title: The oncoprotein gankyrin promotes the development of colitis-associated cancer through activation of STAT3
Authors: Sakurai, Toshiharu
Higashitsuji, Hiroaki
Kashida, Hiroshi
Watanabe, Tomohiro
Komeda, Yoriaki
Nagai, Tomoyuki
Hagiwara, Satoru
Kitano, Masayuki
Nishida, Naoshi
Abe, Takaya
Kiyonari, Hiroshi
Itho, Katsuhiko
Fujita, Jun
Kudo, Masatoshi
Author's alias: 藤田, 潤
Issue Date: 2017
Publisher: Impact Journals, LLC
Journal title: Oncotarget
Volume: 8
Issue: 15
Start page: 24762
End page: 24776
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.
Rights: Copyright: Sakurai et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI(Published Version): 10.18632/oncotarget.14983
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