A definitive role of ornithine decarboxylase in photocarcinogenesis.
Excessive exposure of solar ultraviolet (UV) radiation, particularly its UVB component, to human skin is the major cause for more than a million new cases of cutaneous malignancies diagnosed annually in the United States. Photocarcinogenesis, like other cancers, is a multistep process that includes initiation and promotion. A proper understanding of the molecular events occurring during the tumor promotion phase of photocarcinogenesis could lead to the development of novel approaches for the management of skin cancer. Using a transgenic mouse model (K5/ODC mice), which overexpresses the enzyme ornithine decarboxylase (ODC) in hair follicle keratinocytes, we studied the role of this gene in photocarcinogenesis. A single UVB-exposure of 180 mJ/cm(2) to the transgenic mice resulted in a minimal increase in bifold skin thickness and ODC activity. However, in SKH-1 hairless mice, the most common and highly sensitive model for photocarcinogenesis, and in littermate nontransgenic mice, increases in skin thickness and ODC activity were substantial. In long-term experiments, mice were exposed to 180 mJ/cm(2) of UVB radiation three times a week for 2 weeks (tumor-initiating dose). At 30 weeks after this treatment, in two independent experiments, 40% of the K5/ODC transgenic mice exposed to UVB were found to develop epidermal tumors. The tumors were histologically verified as benign papillomas and squamous cell carcinomas. Interestingly, 100% of the transgenic mice also developed >20 pigmented cysts/mouse, which contained keratinocyte material with increased keratinocytic melanization. Under similar UVB-exposure protocol, the nontransgenic littermates or SKH-1 hairless mice did not develop tumors or pigmented cysts for up to 50 weeks. Oral consumption of alpha-difluoromethylornithine, an irreversible specific inhibitor of ODC, in the drinking water (1% w/v) to the transgenic mice resulted in complete prevention of UVB-mediated tumorigenesis and a substantial decrease in the formation of pigmented cysts (<10 per mouse). These data establish a definitive role of ODC in the promotion phase of photocarcinogenesis.
Ahmad
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Department of Dermatology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106, USA. nxa3@po.cwru.edu
Gilliam
A C
AC
Katiyar
S K
SK
O'Brien
T G
TG
Mukhtar
H
H
D000818:Animals; D003560:Cysts / Q000209:etiology; D051379:Mice; D008812:Mice, Hairless; D018345:Mice, Knockout / Q000235:genetics; D009381:Neoplasms, Radiation-Induced / Q000209:etiology* / Q000473:pathology; D009955:Ornithine Decarboxylase / Q000502:physiology*; D012867:Skin / Q000473:pathology / Q000528:radiation effects; D012871:Skin Diseases / Q000209:etiology; D012878:Skin Neoplasms / Q000209:etiology* / Q000473:pathology; D014466:Ultraviolet Rays
D009955:Ornithine Decarboxylase