Journal Article

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

Minaki, Y, Nakase, H, Chiba, T, Marusawa, H, Takai, A, Watanabe, T, Kinoshita, K, Tsujimoto, G

2012

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Activation-induced cytidine deaminase / Animals / Apoptosis / Cancer / Carcinogenesis / Cecum / Cecum - metabolism / Cell Biology / Colitis / Colitis - complications / Colitis - enzymology / Colon / Colon cancer / Colonic Neoplasms - enzymology / Colonic Neoplasms - genetics / Colorectal cancer / Colorectal carcinoma / Complications and side effects / Cytidine deaminase / Cytidine Deaminase - genetics / Cytidine Deaminase - metabolism / Cytokines / Development and progression / Gene expression / Genetic aspects / Human Genetics / Inflammation / Inflammatory bowel disease / Inflammatory bowel diseases / Inflammatory diseases / Interleukin 10 / Interleukin 12 / Interleukin-10 - genetics / Internal Medicine / Medicine / Medicine & Public Health / Mice / Mucosa / Mutagenesis / Mutation / Neoplasia / Oncology / original-article / Physiological aspects / Prevention / Rodents / Tumor necrosis factor / Tumor Necrosis Factor-alpha - genetics / Tumor necrosis factor-TNF / Tumor necrosis factor-α / Tumor Suppressor Protein p53 - genetics / Tumors