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Targeting activation-induced cytidine deaminase prevents colon cancer development despite persistent colonic inflammation

Oncogene volume 31, pages 1733–1742 (2012)Cite this article

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.

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Abbreviations

AID:

activation-induced cytidine deaminase

cDNA:

complementary DNA

IBD:

inflammatory bowel disease

IFN:

interferon

IL:

interleukin

mAb:

monoclonal antibody

NF:

nuclear factor

RT–PCR:

reverse transcription–PCR

TNF:

tumor necrosis factor

TP53 :

tumor protein p53

WT:

wild type

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Acknowledgements

We thank Dr Keiichiro Suzuki and Dr Tasuku Honjo for critical reading of this manuscript, and Dr Masamichi Muramatsu for providing information of siRNA for AID. This work was supported by grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science; a grant-in-aid for Scientific Research from the Ministry of Health, Labor, and Welfare, Japan; and a research grant of the Princess Takamatsu Cancer Research Fund.

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    A Takai, H Marusawa, Y Minaki, T Watanabe, H Nakase & T Chiba

  2. Shiga Medical Center Research Institute, Moriyama, Japan

    K Kinoshita

  3. Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan

    G Tsujimoto

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  1. A Takai
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Correspondence to H Marusawa.

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Takai, A., Marusawa, H., Minaki, Y. et al. Targeting activation-induced cytidine deaminase prevents colon cancer development despite persistent colonic inflammation. Oncogene 31, 1733–1742 (2012). https://doi.org/10.1038/onc.2011.352

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