Activation-induced cytidine deaminase links between inflammation and the development of colitis-associated colorectal cancers
Activation-induced cytidine deaminase links between inflammation and the development of colitis-associated colorectal cancers
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DOI：
10.1053/j.gastro.2008.06.091
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发表时间：
2008-09-01
期刊：
影响因子：
29.4
通讯作者：
Chiba, Tsutomu
中科院分区：
文献类型：
--
作者：
Endo, Yoko;Marusawa, Hiroyuki;Chiba, Tsutomu
背景与目的：激活诱导型胞苷脱氨酶(AID)最初被认为是免疫球蛋白基因体细胞超突变的诱因。我们最近发现，异位AID表达是细胞编辑机制和高突变频率之间的联系，导致人类癌症的发生。在目前的研究中，我们调查了AID是否可能与结肠炎相关性结直肠癌的发生有关。方法：采用体外培养的结肠细胞，观察促炎症细胞因子刺激下AID的表达及调控。用逆转录病毒系统分析AID对结肠细胞的遗传毒活性。应用免疫组织化学方法对不同类型的人结肠组织标本进行AID免疫组织化学染色。结果：肿瘤坏死因子-a通过I-kappaB-KappaB-信号通路诱导人结肠上皮细胞AID异常表达。此外，在人类炎症性肠病中被激活的T辅助细胞2驱动的细胞因子IL-4和IL-13也诱导了AID的表达。AID在结肠细胞中的异常激活优先诱导TP53基因的遗传突变，而APC基因没有核苷酸变化。免疫组织化学显示，内源性AID蛋白不仅在溃疡性结肠炎患者炎症的结肠黏膜中表达增强，而且在结肠炎相关性结直肠癌的肿瘤病变中也有表达。癌症。结论：我们的研究结果表明，促炎细胞因子介导的AID在结肠上皮细胞中的异常表达是一种将炎症、体细胞突变和结直肠癌发生联系起来的遗传毒性因素。
Background & Aims: Activation-induced cytidine deaminase (AID) was originally identified as an inducer of somatic hypermutations in the immunoglobulin gene. We recently revealed that ectopic AID expression serves as a link between the cellular editing machinery and high mutation frequencies, leading to human cancer development. In the current study, we investigated whether AID might contribute to the development of colitis-associated colorectal cancers. Methods: The expression and regulation of AID in association with proinflammatory cytokine stimulation were investigated in cultured colonic cells. Genotoxic activity of AID in colonic cells was analyzed using retroviral system. Immunohistochemistry for AID was carried out on various human colonic tissues specimens. Results: Tumor necrosis factor-a induced aberrant AID expression via I kappa B kinase-dependent nuclear factor (NF)-kappa B-signaling pathways in human colonic epithelial cells. Moreover, AID expression was also induced in response to the T helper cell 2-driven cytokines interleukin-4 an interleukin-13, which are activated in human inflammatory bowel disease. Aberrant activation of AID in colonic cells preferentially induced genetic mutations in the TP53 gene, whereas there were no nucleotide alterations of the APC gene. Immunohistochemistry revealed enhanced expression of endogenous AID protein not only in the inflamed colonic mucosa of ulcerative colitis patients but also in tumor lesions of colitis-associated colorectal. cancers. Conclusions: Our findings indicate that proinflammatory cytokine-mediated aberrant expression of AID in colonic epithelial cells is a genotoxic factor linking inflammation, somatic mutations, and colorectal cancer development.