Involvement of activation-induced cytidine deaminase in the development of colitis-associated colorectal cancers.
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-α induced strong aberrant expression of AID via IκB kinase-dependent NF-κB-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.
Endo
Yoko
Y
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
Marusawa
Hiroyuki
H
Chiba
Tsutomu
T
D003093:Colitis, Ulcerative / Q000150:complications* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation / Q000150:complications / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D012306:Risk; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D016207:Cytokines; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase