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Analysis of p53 Tumor Suppressor Gene, H-ras Protooncogene and Proliferating Cell Nuclear Antigen (PCNA) in Squamous Cell Carcinomas of HRA/Skh Mice Following Exposure to 8-Methoxypsoralen (8-MOP) and UVA Radiation (PUVA Therapy)

¹ Laboratory of Experimental Pathology
² Toxicology Operation Branch and
³ Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA

Correspondence: Address correspondence to: Robert C. Sills, Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, National Institute of Health, 111 T. W. Alexander Drive, P.O. Box 12233, Mail Drop B3-08, Research Triangle Park, North Carolina 27709, USA; e-mail:sills{at}niehs.nih.gov

Treatment with 8-methoxypsoralen (8-MOP) and ultraviolet radiation (primarily UVA), called PUVA therapy, has been used to treat different chronic skin diseases but led to a significant increased risk for skin cancer. The National Toxicology Program (NTP) performed a study in mice treated with PUVA that showed a significant increase in squamous cell carcinomas of the skin. In the present study, we evaluated the protein expression of p53 and PCNA and DNA mutations of p53 and H-ras genes in both hyperplastic and neoplastic squamous cell lesions from the NTP study. By immunohistochemical staining, protein expression of both p53 and PCNA was detected in 3/16 (19%) of hyperplastic lesions and 14/17 (82%) of SCCs in groups treated with both 8-MOP and UVA. The mutation frequency of p53 in SCCs from mice administered 8-MOP plus UVA was 15/17 (88%) with a predominant distribution of mutations in exon 6 (14/15 – 93%). No H-ras mutations were detected in the hyperplastic lesions/tumors. The mutagenic effect of PUVA on the p53 tumor suppressor gene may lead to a conformational modification and inactivation of the p53 protein, which are considered critical steps in PUVA-induced skin carcinogenesis. The p53 mutational frequency and patterns from our study were different from those reported in human PUVA-type tumors.

Key Words: PUVA • p53 • PCNA • mutation • skin squamous cell carcinoma (SCC) • thymine

Abbreviations: 8-MOP, 8-methoxypsoralen • A, C, G, T, adenine, cytosine, guanine, thymine • group C, control • group F, exposed to filtered UV • group PUVA-F, exposed to 8-Methoxypsoralen and filtered UV • group PUVA-U, exposed to 8-Methoxypsoralen and unfiltered UV • group U, exposed to unfiltered UV • HRA/Skh, hairless phenotype mouse strain • IARC, International Agency for Research on Cancer • NTP, National Toxicology Program • PCNA, proliferating cell nuclear antigen • PUVA, Psoralen (8-MOP) with UVA light • SCC, squamous cell carcinoma • SCH, squamous cell hyperplasia • SCP, squamous cell papilloma • UVA, light ultraviolet radiation of the A group (wavelength 320–400 nm)

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