Activation-induced cytidine deaminase links between inflammation and the development of colitis-associated colorectal cancers.
OBJECTIVE
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-alpha induced aberrant AID expression via IkappaB kinase-dependent nuclear factor (NF)-kappaB-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 and 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.
Endo
Yoko
Y
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Marusawa
Hiroyuki
H
Kou
Tadayuki
T
Nakase
Hiroshi
H
Fujii
Shigehiko
S
Fujimori
Takahiro
T
Kinoshita
Kazuo
K
Honjo
Tasuku
T
Chiba
Tsutomu
T
D000328:Adult; D000368:Aged; D003093:Colitis, Ulcerative / Q000150:complications / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D003564:Cytidine Deaminase / Q000378:metabolism*; D005260:Female; D017491:Genes, APC; D016259:Genes, myc / Q000235:genetics; D016158:Genes, p53 / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology; D015848:Interleukin-5 / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D018793:Interleukin-13; D015848:Interleukin-5; D016328:NF-kappa B; D050800:STAT6 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase