title: Stress response protein cirp links inflammation and tumorigenesis in colitis-associated cancer.
abstract: Colitis-associated cancer (CAC) is caused by chronic intestinal inflammation and is reported to be associated with refractory inflammatory bowel disease (IBD). Defective apoptosis of inflammatory cell populations seems to be a relevant pathogenetic mechanism in refractory IBD. We assessed the involvement of stress response protein cold-inducible RNA-binding protein (Cirp) in the development of intestinal inflammation and CAC. In the colonic mucosa of patients with ulcerative colitis, expression of Cirp correlated significantly with the expression of TNFα, IL23/IL17, antiapoptotic proteins Bcl-2 and Bcl-xL, and stem cell markers such as Sox2, Bmi1, and Lgr5. The expression of Cirp and Sox2 was enhanced in the colonic mucosae of refractory ulcerative colitis, suggesting that Cirp expression might be related to increased cancer risk. In human CAC specimens, inflammatory cells expressed Cirp protein. Cirp(-/-) mice given dextran sodium sulfate exhibited decreased susceptibility to colonic inflammation through decreased expression of TNFα, IL23, Bcl-2, and Bcl-xL in colonic lamina propria cells compared with similarly treated wild-type (WT) mice. In the murine CAC model, Cirp deficiency decreased the expression of TNFα, IL23/IL17, Bcl-2, Bcl-xL, and Sox2 and the number of Dclk1(+) cells, leading to attenuated tumorigenic potential. Transplantation of Cirp(-/-) bone marrow into WT mice reduced tumorigenesis, indicating the importance of Cirp in hematopoietic cells. Cirp promotes the development of intestinal inflammation and colorectal tumors through regulating apoptosis and production of TNFα and IL23 in inflammatory cells.
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, Osaka-Sayama, Japan. sakurai@med.kindai.ac.jp.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Sakurai
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, Osaka-Sayama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kashida
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, Osaka-Sayama, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Hagiwara
authors.affiliation: Department of Surgery, Osaka University, Osaka, Japan.
authors.forename: Tsunekazu
authors.initials: T
authors.lastname: Mizushima
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University, Osaka, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Iijima
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, Osaka-Sayama, Japan.
authors.forename: Naoshi
authors.initials: N
authors.lastname: Nishida
authors.affiliation: Department of Clinical Molecular Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Higashitsuji
authors.affiliation: Department of Clinical Molecular Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Fujita
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, Osaka-Sayama, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kudo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics; D003092:Colitis / Q000150:complications / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000235:genetics* / Q000473:pathology; D053760:Interleukin-23 Subunit p19; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis; D016601:RNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C491390:CIRBP protein, human; C508840:IL23A protein, human; D053760:Interleukin-23 Subunit p19; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha