1. 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).
- Author
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Lambertini L, Surin K, Ton TV, Clayton N, Dunnick JK, Kim Y, Hong HH, Devereux TR, and Sills RC
- Subjects
- Animals, Carcinoma, Squamous Cell etiology, Carcinoma, Squamous Cell pathology, DNA Mutational Analysis, DNA, Neoplasm analysis, Hyperplasia genetics, Hyperplasia metabolism, Hyperplasia pathology, Immunoenzyme Techniques, Methoxsalen toxicity, Mice, Mice, Nude, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) metabolism, Skin metabolism, Skin pathology, Skin Neoplasms etiology, Skin Neoplasms pathology, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Ultraviolet Rays adverse effects, Carcinoma, Squamous Cell genetics, Genes, p53, Genes, ras, Mutation, PUVA Therapy adverse effects, Proliferating Cell Nuclear Antigen metabolism, Skin Neoplasms genetics
- Abstract
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.
- Published
- 2005
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