Genetic ablation of caspase-7 promotes solar-simulated light-induced mouse skin carcinogenesis: the involvement of keratin-17.
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.
The Hormel Institute, University of Minnesota, 801 16th Ave. NE, Austin, MN 55912, USA, College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-743, South Korea.
Mee-Hyun
MH
Lee
The Hormel Institute, University of Minnesota, 801 16th Ave. NE, Austin, MN 55912, USA.
Do Young
DY
Lim
The Hormel Institute, University of Minnesota, 801 16th Ave. NE, Austin, MN 55912, USA, Center for Laboratory Animal Resources, School of Animal BT Science and.
Myoung Ok
MO
Kim
The Hormel Institute, University of Minnesota, 801 16th Ave. NE, Austin, MN 55912, USA, Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
Sung-Young
SY
Lee
The Hormel Institute, University of Minnesota, 801 16th Ave. NE, Austin, MN 55912, USA, Program in Biomedical Informatics and Computational Biology, University of Minnesota, Minneapolis, MN 55455, USA.
Seung Ho
SH
Shin
Department of Biochemistry, School of Dentistry, Kyungpook National University, Daegu 702-701, South Korea.
Jae Young
JY
Kim
The Hormel Institute, University of Minnesota, 801 16th Ave. NE, Austin, MN 55912, USA, Center for Laboratory Animal Resources, School of Animal BT Science and.
Sung-Hyun
SH
Kim
The Hormel Institute, University of Minnesota, 801 16th Ave. NE, Austin, MN 55912, USA, Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, South Korea.
Dong Joon
DJ
Kim
The Hormel Institute, University of Minnesota, 801 16th Ave. NE, Austin, MN 55912, USA, Functionality Evaluation Research Group, Korea Food Research Institute, Seongnam 463-746, South Korea.
Sung Keun
SK
Jung
The Hormel Institute, University of Minnesota, 801 16th Ave. NE, Austin, MN 55912, USA.
Ke
K
Yao
College of Pharmacy, Keimyung University, Daegu 704-701, South Korea and.
Joydeb Kumar
JK
Kundu
College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-743, South Korea.
Hye Suk
HS
Lee
College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-743, South Korea.
Cheol-Jung
CJ
Lee
University of Arizona Cancer Center, Tucson, AZ 85704, USA.
Sally E
SE
Dickinson
University of Arizona Cancer Center, Tucson, AZ 85704, USA.
David
D
Alberts
University of Arizona Cancer Center, Tucson, AZ 85704, USA.
G Timothy
GT
Bowden
University of Arizona Cancer Center, Tucson, AZ 85704, USA.
Steven
S
Stratton
University of Arizona Cancer Center, Tucson, AZ 85704, USA.
Clara
C
Curiel
University of Arizona Cancer Center, Tucson, AZ 85704, USA.
Janine
J
Einspahr
The Hormel Institute, University of Minnesota, 801 16th Ave. NE, Austin, MN 55912, USA.
Ann M
AM
Bode
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
Young-Joon
YJ
Surh
The Hormel Institute, University of Minnesota, 801 16th Ave. NE, Austin, MN 55912, USA, College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-743, South Korea, zgdong@hi.umn.edu yongyeon@catholic.ac.kr.
Yong-Yeon
YY
Cho
The Hormel Institute, University of Minnesota, 801 16th Ave. NE, Austin, MN 55912, USA, Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea, zgdong@hi.umn.edu.
Zigang
Z
Dong
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D053179:Caspase 7 / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004817:Epidermis / Q000201:enzymology / Q000473:pathology / Q000528:radiation effects; D005260:Female; D055786:Gene Knockout Techniques; D015603:Keratinocytes / Q000201:enzymology; D007633:Keratins / Q000502:physiology*; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D059748:Proteolysis; D011833:Radiation Injuries, Experimental / Q000201:enzymology*; D012878:Skin Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D013472:Sunlight / Q000009:adverse effects*; D047368:Tumor Burden
C118917:Krt17 protein, mouse; D007633:Keratins; C505524:Casp7 protein, mouse; D053179:Caspase 7