| Targeting activation-induced cytidine deaminase prevents colon cancer development despite persistent colonic inflammation. | |
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MedLine Citation:
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PMID: 21841819 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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.Oncogene advance online publication, 15 August 2011; doi:10.1038/onc.2011.352. |
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Authors:
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A Takai; H Marusawa; Y Minaki; T Watanabe; H Nakase; K Kinoshita; G Tsujimoto; T Chiba |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-8-15 |
Journal Detail:
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Title: Oncogene Volume: - ISSN: 1476-5594 ISO Abbreviation: - Publication Date: 2011 Aug |
Date Detail:
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Created Date: 2011-8-15 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8711562 Medline TA: Oncogene Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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