Although most human skin cancers are the result of exposure to UV light, a small number are caused by UV-independent mechanisms. Chronic inflammation in the epidermis, triggered by a variety of external or internal factors, is known to be a key risk factor in the development of these UV-independent skin cancers. What is not known, however, is how local inflammation in the skin leads to DNA mutation and cancer. Activation-induced cytidine deaminase (AID) was originally identified for its role in generating antibody diversity in B-cells via DNA mutation and recombination. Further research has implicated AID in the development of hepatocellular carcinoma, gastric cancer, and colorectal cancer. Taichiro Nonaka and colleagues at Shiga Medical Research Institute and Kyoto University Graduate School of Medicine now find that AID plays a role in the development of UV-independent skin cancer. Using transgenic overexpression and knockouts, the authors determined that AID is a crucial factor in the initiation, promotion, and progression of chemically induced skin tumors in mice. Importantly, the authors found that the tumors of these mice have mutations that are characteristic of those that can be produced by AID. The authors go on to show that AID is induced in the skin of mice in an inflammatory stimulus-dependent manner and that AID is expressed in a variety of human skin cancers and pre-cancerous lesions. The resulting model places AID as a key driver of inflammation-induced mutations and tumor progression in non-UV skin cancer. The accompanying image shows H&E (left panel) and anti-AID staining (right panel) of a skin tumor from a mouse overexpressing AID in epidermal basal cells. Note the strong expression of AID in the right panel.
Most skin cancers develop as the result of UV light–induced DNA damage; however, a substantial number of cases appear to occur independently of UV damage. A causal link between UV-independent skin cancers and chronic inflammation has been suspected, although the precise mechanism underlying this association is unclear. Here, we have proposed that activation-induced cytidine deaminase (AID, encoded by
Taichiro Nonaka, Yoshinobu Toda, Hiroshi Hiai, Munehiro Uemura, Motonobu Nakamura, Norio Yamamoto, Ryo Asato, Yukari Hattori, Kazuhisa Bessho, Nagahiro Minato, Kazuo Kinoshita