title: Targeting activation-induced cytidine deaminase prevents colon cancer development despite persistent colonic inflammation.
abstract: Inflammatory bowel disease (IBD) is an important etiologic factor in the development of colorectal cancer. However, the mechanism underlying carcinogenesis through chronic inflammation is still unknown. Activation-induced cytidine deaminase (AID) is induced by the inflammation and involved in various human carcinogenesis via its mutagenic activity. In the current study, we investigated whether the inflammation/AID axis plays an integral role in the development of colitis-associated cancers. Inflammation in the cecum was more severe than that in other colonic regions, and endogenous AID expression was enhanced most prominently in the inflamed cecal mucosa of interleukin (IL)-10(-/-) mice. Blockade of tumor necrosis factor (TNF)-α and IL-12 significantly suppressed AID expression. Although proinflammatory cytokine expression was comparable between IL-10(-/-)AID(+/+) and IL-10(-/-)AID(-/-) mice, sequencing analyses revealed a significantly lower incidence of somatic mutations in Trp53 gene in the colonic mucosa of IL-10(-/-)AID(-/-) than IL-10(-/-)AID(+/+) mice. Colon cancers spontaneously developed in the cecum in 6 of 22 (27.2%) IL-10(-/-)AID(+/+) mice. In contrast, none of the IL-10(-/-)AID(-/-) mice developed cancers except only one case of neoplasia in the distal colon. These findings suggest that the proinflammatory cytokine-induced aberrant production of AID links colonic inflammation to an enhanced genetic susceptibility to oncogenic mutagenesis. Targeting AID could be a novel strategy to prevent colitis-associated colon carcinogenesis irrespective of ongoing colonic inflammation.
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Takai
authors.forename: H
authors.initials: H
authors.lastname: Marusawa
authors.forename: Y
authors.initials: Y
authors.lastname: Minaki
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
authors.forename: H
authors.initials: H
authors.lastname: Nakase
authors.forename: K
authors.initials: K
authors.lastname: Kinoshita
authors.forename: G
authors.initials: G
authors.lastname: Tsujimoto
authors.forename: T
authors.initials: T
authors.lastname: Chiba
mesh_terms: D000818:Animals; D002432:Cecum / Q000378:metabolism; D003092:Colitis / Q000150:complications / Q000201:enzymology*; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics; D051379:Mice; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D016753:Interleukin-10; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase