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AIDing and abetting UV-independent skin cancer

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.

Published March 14, 2016, by Brian P. Head

Scientific Show StopperOncology

Related articles

Involvement of activation-induced cytidine deaminase in skin cancer development
Taichiro Nonaka, … , Nagahiro Minato, Kazuo Kinoshita
Taichiro Nonaka, … , Nagahiro Minato, Kazuo Kinoshita
Published April 1, 2016; First published March 14, 2016
Citation Information: J Clin Invest. 2016;126(4):1367-1382. https://doi.org/10.1172/JCI81522.
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Categories: Research Article Oncology

Involvement of activation-induced cytidine deaminase in skin cancer development

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Abstract

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 AICDA) links chronic inflammation and skin cancer. We demonstrated that Tg mice expressing AID in the skin spontaneously developed skin squamous cell carcinoma with Hras and Trp53 mutations. Furthermore, genetic deletion of Aicda reduced tumor incidence in a murine model of chemical-induced skin carcinogenesis. AID was expressed in human primary keratinocytes in an inflammatory stimulus–dependent manner and was detectable in human skin cancers. Together, the results of this study indicate that inflammation-induced AID expression promotes skin cancer development independently of UV damage and suggest AID as a potential target for skin cancer therapeutics.

Authors

Taichiro Nonaka, Yoshinobu Toda, Hiroshi Hiai, Munehiro Uemura, Motonobu Nakamura, Norio Yamamoto, Ryo Asato, Yukari Hattori, Kazuhisa Bessho, Nagahiro Minato, Kazuo Kinoshita

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