The oncoprotein gankyrin promotes the development of colitis-associated cancer through activation of STAT3.
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.
Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
Toshiharu
T
Sakurai
Department of Clinical Molecular Biology, Kyoto University, Kyoto, Japan.
Hiroaki
H
Higashitsuji
Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
Hiroshi
H
Kashida
Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
Tomohiro
T
Watanabe
Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
Yoriaki
Y
Komeda
Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
Tomoyuki
T
Nagai
Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
Satoru
S
Hagiwara
Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
Masayuki
M
Kitano
Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
Naoshi
N
Nishida
Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe, Japan.
Takaya
T
Abe
Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe, Japan.|Animal Resource Development Unit, RIKEN Center for Life Science Technologies, Kobe, Japan.
Hiroshi
H
Kiyonari
Department of Clinical Molecular Biology, Kyoto University, Kyoto, Japan.
Katsuhiko
K
Itoh
Department of Clinical Molecular Biology, Kyoto University, Kyoto, Japan.
Jun
J
Fujita
Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
Masatoshi
M
Kudo
D000818:Animals; D003092:Colitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046988:Proteasome Endopeptidase Complex / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D020381:Interleukin-17; C403591:PSMD10 protein, human; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C525549:gankyrin protein, mouse; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D046988:Proteasome Endopeptidase Complex
Bmi1; IBD; IL-17; TNF; treatment resistance