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

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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Figure 2

Initiation and promotion of skin tumors by aberrant AID expression in a chemically induced skin carcinogenesis model.

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Initiation and promotion of skin tumors by aberrant AID expression in a ...
(A) Representative photographs of skin tumors in mice. For the DMBA-plus-TPA groups, a single 260-nmol dose of DMBA was applied to the dorsal skin of the mice, and 2 weeks after initiation, 16 nmol TPA was applied twice weekly for the duration of the experiments. For the DMBA-alone group, a single 260-nmol dose of DMBA was applied. For the TPA-alone group, 16 nmol TPA was applied twice weekly for the duration of the experiment. Each photograph was taken 20 weeks after TPA treatment, except the photograph of the K14-AID–Tg mice treated with DMBA (22 weeks) or TPA alone (29 weeks). (B) Schematic representation of multistep chemically induced skin carcinogenesis. Skin tumors develop following single DMBA exposure and both subsequent and multiple TPA exposures. (C) Average volume of skin tumors in K14-AID–Tg mice treated with DMBA and TPA (mean ± SD). *P < 0.05, by Welch’s t test. (D–I) Average number of skin tumors that developed over time in mice treated with DMBA and/or TPA (mean ± SD). AID+/+, WT; AID+/−, heterozygote; AID−/−, deficient mice. *P < 0.05, by Welch’s t test.