Targeting activation-induced cytidine deaminase prevents colon cancer development despite persistent colonic inflammation
Targeting activation-induced cytidine deaminase prevents colon cancer development despite persistent colonic inflammation
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DOI：
10.1038/onc.2011.352
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发表时间：
2012-03-01
期刊：
影响因子：
8
通讯作者：
Chiba, T.
中科院分区：
文献类型：
--
作者：
Takai, A.;Marusawa, H.;Chiba, T.
炎症性肠病（IBD）是结直肠癌发生发展的重要病因。然而，通过慢性炎症致癌的潜在机制仍然未知。激活诱导的胞苷脱氨酶（AID）是由炎症诱导的，并通过其致突变活性参与多种人类癌症的发生。在目前的研究中，我们调查了炎症/AID轴是否在结肠炎相关癌症的发展中起着不可或缺的作用。盲肠的炎症比其他结肠区域更严重，并且内源性AID表达在白细胞介素（IL）-10（-/-）小鼠的炎症盲肠粘膜中最显著地增强。阻断肿瘤坏死因子（TNF）-α和IL-12显著抑制AID表达。尽管IL-10（-/-）AID（+/+）和IL-10（-/-）AID（-/-）小鼠之间的促炎细胞因子表达相当，但测序分析显示IL-10（-/-）AID（-/-）小鼠结肠粘膜中Trp 53基因的体细胞突变发生率显著低于IL-10（-/-）AID（+/+）小鼠。22只IL-10（-/-）AID（+/+）小鼠中有6只（27.2%）在盲肠中自发发生结肠癌。相比之下，IL-10（-/-）AID（-/-）小鼠中没有一只发生癌症，除了在远端结肠中仅发生一例肿瘤形成。这些发现表明，促炎性精氨酸诱导的AID异常产生将结肠炎症与致癌突变的遗传易感性增强联系起来。靶向AID可能是一种新的策略，以防止结肠炎相关的结肠癌的发生，而不管正在进行的结肠炎症。Oncogene（2012）31，1733-1742; doi：10.1038/onc.2011.352; 2011年8月15日在线发表
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)-alpha 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 (2012) 31, 1733-1742; doi:10.1038/onc.2011.352; published online 15 August 2011