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).
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.
Lambertini
Luca
L
Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Surin
Kezia
K
Ton
Thai-Vu T
TV
Clayton
Natasha
N
Dunnick
June K
JK
Kim
Yongbaek
Y
Hong
Hue-Hua L
HH
Devereux
Theodora R
TR
Sills
Robert C
RC
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis; D016158:Genes, p53; D011905:Genes, ras; D006965:Hyperplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007124:Immunoenzyme Techniques; D008730:Methoxsalen / Q000633:toxicity; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D011701:PUVA Therapy / Q000009:adverse effects*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects
D004273:DNA, Neoplasm; D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras); D008730:Methoxsalen