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

Spontaneous skin carcinogenesis in AID-Tg mice.

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Spontaneous skin carcinogenesis in AID-Tg mice. (A) Representative image...
(A) Representative images of spontaneously developed melanomas in the auricles of CAG-AID–Tg mice and psoriasis-like skin lesions in TPA-treated CAG-AID–Tg nu/nu mice. (B) Generation of keratin 14 promoter–driven AID-Tg mice on an FVB/N (homozygous Ptch1 T1267N) background. (C) Relative Aicda mRNA expression in K14-AID–Tg epidermis (mean ± SD, n = 3). K14-AIDhi and K14-AIDlo indicate mice with high and low K14-AID transgene expression, respectively. (D) Anti-AID staining of the epidermis from K14-AIDhi mice. Bracket indicates the epidermis. Scale bar: 100 μm. (E) Representative images of spontaneous skin and oral cancers on K14-AIDhi mice. (F) H&E and anti-AID staining of spontaneous skin cancer from K14-AIDhi mice. Scale bar: 500 μm. (G) Average number of skin tumors that developed spontaneously in K14-AID–Tg mice (mean ± SD). All mouse groups had homozygous Ptch1 T1267N alleles. nu/nu, mice with homozygous nude alleles. (H) Incidence of skin tumors that developed spontaneously in K14-AID–Tg mice. (I) Kaplan-Meier survival curves for K14-AID–Tg mice. *P < 0.0001, by log-rank test.