Role of activation-induced cytidine deaminase in inflammation-associated cancer development

Abstract

Human cancer is a genetic disease resulting from the stepwise accumulation of genetic alterations in various tumor-related genes. Normal mutation rates, however, cannot account for the abundant genetic changes accumulated in tumor cells, suggesting that certain molecular mechanisms underlie such a large number of genetic alterations. Activation-induced cytidine deaminase (AID), a nucleotide-editing enzyme that triggers DNA alterations and double-strand DNA breaks in the immunoglobulin gene, has been identified in activated B lymphocytes. Recent studies revealed that AID-mediated genotoxic effects target not only immunoglobulin genes but also a variety of other genes in both B lymphocytes and non-lymphoid cells. Consistent with the finding that several transcription factors including nuclear factor-κB (NF-κB) mediate AID expression in B cells, proinflammatory cytokine stimulation of several types of gastrointestinal epithelial cells, such as gastric, colonic, hepatic, and biliary epithelium, induces aberrant AID expression through the NF-κB signaling pathway. In vivo studies revealed that constitutive AID expression promotes the tumorigenic pathway by enhancing the susceptibility to mutagenesis in a variety of epithelial organs. The activity of AID as a genome mutator provides a new avenue for studies aimed at understanding mutagenesis mechanisms during carcinogenesis.