Involvement of activation-induced cytidine deaminase in the development of colitis-associated colorectal cancers
Involvement of activation-induced cytidine deaminase in the development of colitis-associated colorectal cancers
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DOI：
10.1007/s00535-010-0326-1
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发表时间：
2011-01-01
影响因子：
6.3
通讯作者：
Chiba, Tsutomu
中科院分区：
文献类型：
--
作者：
Endo, Yoko;Marusawa, Hiroyuki;Chiba, Tsutomu
慢性炎症性肠病（IBD）是大肠癌发生发展的重要病因。然而，通过慢性炎症发展结直肠癌的潜在机制尚不清楚。激活诱导的胞苷脱氨酶（AID）最初被鉴定为免疫球蛋白基因体细胞高突变的诱导物。我们最近发现AID表达的致突变活性将炎症与癌症的发展联系起来。异常AID表达由人肝细胞中的丙型肝炎病毒感染或人胃上皮细胞中的幽门螺杆菌感染触发，并导致各种肿瘤相关基因的体细胞突变的产生。在这里，我们回顾了我们的研究结果，如何艾滋病有助于结肠炎相关的结直肠癌（CAC）的发展。免疫组化结果显示，内源性AID蛋白不仅在溃疡性结肠炎患者的炎症结肠粘膜中表达增强，而且在CAC肿瘤病变中也表达增强。促炎细胞因子TNF-α通过I κ B激酶依赖性NF-κ B信号通路诱导人结肠上皮细胞中AID的强烈异常表达此外，辅助性T细胞2驱动的细胞因子IL-4和IL-13也会引发AID表达，这些细胞因子在人IBD中被激活。在结肠细胞中AID的异常激活优先诱发TP 53基因的基因突变，而APC基因没有核苷酸改变。这些发现表明，促炎性精氨酸介导的AID在结肠上皮细胞中的异常表达作为基因毒性因子发挥作用，其在慢性结肠炎症期间增强遗传不稳定性，导致CAC发展。
Chronic inflammatory bowel disease (IBD) is an important etiologic factor in the development of colorectal cancer. However, the mechanism underlying the development of colorectal cancers through chronic inflammation is not known. Activation-induced cytidine deaminase (AID) was originally identified as an inducer of somatic hypermutation in the immunoglobulin gene. We recently found that the mutagenic activity of AID expression links inflammation to the development of cancer. Aberrant AID expression is triggered by hepatitis C virus infection in human hepatocytes or Helicobacter pylori infection in human gastric epithelial cells, and leads to the generation of somatic mutations in various tumor-related genes. Here, we review our findings relating to how AID contributes to the development of colitis-associated colorectal cancers (CACs). Immunohistochemistry revealed the enhanced expression of endogenous AID protein in not only in the inflamed colonic mucosa of ulcerative colitis patients but also CAC tumor lesions. Pro-inflammatory cytokine TNF-alpha induced strong aberrant expression of AID via I kappa B kinase-dependent NF-kappa B-signaling pathways in human colonic epithelial cells. Furthermore, AID expression was also elicited in response to the T helper cell-2-driven cytokines IL-4 and IL-13, which are activated in human IBD. Aberrant activation of AID in colonic cells preferentially evoked genetic mutations in the TP53 gene, whereas there were no nucleotide alterations of the APC gene. These findings suggested that pro-inflammatory cytokine-mediated aberrant expression of AID in colonic epithelial cells plays a role as a genotoxic factor that enhances genetic instability during chronic colonic inflammation, leading to CAC development.