Genetic ablation of caspase-7 promotes solar-simulated light-induced mouse skin carcinogenesis: the involvement of keratin-17

Mee Hyun Lee, Do Young Lim, Myoung Ok Kim, Sung Young Lee, Seung Ho Shin, Jae Young Kim, Sung Hyun Kim, Dong Joon Kim, Sung Keun Jung, Ke Yao, Joydeb Kumar Kundu, Hye Suk Lee, Cheol Jung Lee, Sally E Dickinson, David S Alberts, G. Timothy Bowden, Steven P Stratton, Clara N Curiel, Janine G Einspahr, Ann M. BodeYoung Joon Surh, Yong Yeon Cho, Zigang Dong

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Solar ultraviolet irradiation is an environmental carcinogen that causes skin cancer. Caspase-7 is reportedly expressed at reduced levels in many cancers. The present study was designed to examine the role of caspase-7 in solar-simulated light (SSL)-induced skin cancer and to elucidate its underlying molecular mechanisms. Our study revealed that mice with genetic deficiency of caspase-7 are highly susceptible to SSL-induced skin carcinogenesis. Epidermal hyperplasia, tumor volume and the average number of tumors were significantly increased in caspase-7 knockout (KO) mice compared with SKH1 wild-type mice irradiated with SSL. The expression of cell proliferation markers, such as survivin and Ki-67, was elevated in SSL-irradiated skin of caspase-7 KO mice compared with those observed in SSL-exposed wild-type SKH1 mouse skin. Moreover, SSL-induced apoptosis was abolished in skin from caspase-7 KO mice. Two-dimensional gel electrophoresis, followed by matrix-assisted laser desorption/ionization-time-of-flight analysis of skin tissue lysates from SSL-irradiated SKH1 wild-type and caspase-7 KO mice revealed an aberrant induction of keratin-17 in caspase-7 KO mice. Immunohistochemical analysis of skin tumors also showed an increase of keratin-17 expression in caspase-7 KO mice compared with SKH1 wild-type mice. The expression of keratin-17 was also elevated in SSL-irradiated caspase-7 KO keratinocytes as well as in human basal cell carcinomas. The in vitro caspase activity assay showed keratin-17 as a substrate of caspase-7, but not caspase-3. Overall, our study demonstrates that genetic loss of caspase-7 promotes SSL-induced skin carcinogenesis by blocking caspase-7-mediated cleavage of keratin-17.

Original languageEnglish (US)
Pages (from-to)1372-1380
Number of pages9
JournalCarcinogenesis
Volume36
Issue number11
DOIs
StatePublished - Nov 1 2015

ASJC Scopus subject areas

  • Cancer Research

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    Lee, M. H., Lim, D. Y., Kim, M. O., Lee, S. Y., Shin, S. H., Kim, J. Y., Kim, S. H., Kim, D. J., Jung, S. K., Yao, K., Kundu, J. K., Lee, H. S., Lee, C. J., Dickinson, S. E., Alberts, D. S., Bowden, G. T., Stratton, S. P., Curiel, C. N., Einspahr, J. G., ... Dong, Z. (2015). Genetic ablation of caspase-7 promotes solar-simulated light-induced mouse skin carcinogenesis: the involvement of keratin-17. Carcinogenesis, 36(11), 1372-1380. https://doi.org/10.1093/carcin/bgv110