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

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.

• Authors: 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 Alberts, G Timothy Bowden, Steven Stratton, Clara Curiel, Janine Einspahr, Ann M Bode, Young-Joon Surh, Yong-Yeon Cho, Zigang Dong
• Journal: Carcinogenesis (Carcinogenesis) Vol. 36 Issue 11 Pg. 1372-80 (Nov 2015) ISSN: 1460-2180 [Electronic] England
• PMID: 26271098 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Krt17 protein, mouse
• Keratins
• Casp7 protein, mouse
• Caspase 7

Topics

• Animals
• Carcinoma, Squamous Cell (enzymology, genetics, pathology)
• Caspase 7 (genetics, metabolism)
• Cells, Cultured
• Epidermis (enzymology, pathology, radiation effects)
• Female
• Gene Knockout Techniques
• Keratinocytes (enzymology)
• Keratins (physiology)
• Male
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Proteolysis
• Radiation Injuries, Experimental (enzymology)
• Skin Neoplasms (enzymology, genetics, pathology)
• Sunlight (adverse effects)
• Tumor Burden