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.
View: Text | PDF
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

×

Figure 4

Molecular characterization of spontaneous SCC in K14-AID–Tg mice.

Options: View larger image (or click on image) Download as PowerPoint
Molecular characterization of spontaneous SCC in K14-AID–Tg mice. (A) Co...
(A) Codon distribution of Hras1 somatic mutations. Black circles indicate nonsynonymous mutations. The number above each black circle indicates the codon number. (B) Base substitution patterns identified in Hras1 in spontaneous and TPA-induced SCC. (C) Codon distribution of Trp53 somatic mutations. Black and white circles and gray rectangles indicate nonsynonymous, synonymous, and frameshift mutations, respectively. Frequency of TP53 somatic mutations in human skin SCC from the IARC TP53 database juxtaposed for comparison with distributions and hot spots seen in K14-AID–Tg mice. The top 4 codon numbers of mutations in human skin SCC are shown. (D) Base substitution patterns and frequency of the nucleotide 5′-flanking C-to-T transition in Trp53 in spontaneously developed SCC. The number in the center of the pie chart is the sum of the C-to-T and G-to-A changes. (E–H) Correlations of transcript levels between the K14-AID transgene and Ccnd1, Egfr, Trp53, and Pten, respectively, in spontaneous SCC. Pearson’s correlation statistic was used to measure the extent of the relationships between the expression levels of 2 genes. In A–D, data points indicate the individual K14-AID–Tg mice listed in Supplemental Table 2. (I) IHC of spontaneous SCC developed in K14-AID–Tg mice. Scale bar: 20 μm.