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Carcinogenesis Advance Access published online on June 18, 2009
Carcinogenesis, doi:10.1093/carcin/bgp146
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Increased skin carcinogenesis in caspase-activated Dnase knockout mice

Bin Yan1,3,¶, Huili Wang2,¶, Donghua Xie2, Nobuko Wakamatsu4, Mitchell S. Anscher1, Mark W. Dewhirst3, Ron E. J. Mitchel5, Benny J. Chen2 and Chuan-Yuan Li3,6,*

1 Department of Radiation Oncology, Virginia Commonwealth University Medical Center, Richmond, VA 23298
2 Department of Medicine, Duke University Medical Center, Durham, NC 27710
3 Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710
4 Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709
5 Radiation Biology and Health Physics Branch, Atomic Energy of Canada Limited, Chalk River Laboratories, Chalk River, ON, K0J 1J0, Canada
6 Dept. of Radiation Oncology, University of Colorado Health Sciences Center, Aurora, CO 80045

* Correspondence Chuan-Yuan Li, Ph.D., Dept. of Radiation Oncology, University of Colorado Health Sciences Center, P.O. Box 6511, Mail Stop 8123, Aurora, CO 80045, Tel: (303) 724-1542, Fax: (303) 724-1554, Email: Chuan.Li{at}UCHSC.edu

Caspase-activated Dnase(CAD), also called DNA fragmentation factor(DFF), is the enzyme responsible for DNA fragmentation during apoptosis, a hallmark of programmed cell death. CAD/DFF has been shown to suppress radiation-induced carcinogenesis by preventing genomic instability in cells. In this study, we have investigated the role of CAD in chemical carcinogenesis using CAD-null mice and two-stage model of skin carcinogenesis. After topical treatment of mouse skin with dimethylbenzanthracene (DMBA) as an initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoting agent, there was a 4 fold increase in the number of papillomas per mouse and 50.8% increase in the incidence of papilloma formation in the CAD-knockout mice compared with wild type littermates. The papillomas in CAD-null mice grew faster and reached larger sizes. These data indicate that loss of CAD function enhances tumorigenesis induced by a chemical carcinogen in the DMBA/TPA two-stage model of skin carcinogenesis in mice.

Both authors contributed equally to this work.

Received January 31, 2008; revised September 9, 2008; accepted June 10, 2009.


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