MECHANISMS OF INDUCTION OF SKIN CANCERS BY UV LIGHT

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Ultraviolet radiation (UV) present in sunlight is known to be responsible for the induction of most skin cancers in humans. Since cancers of the skin are the most prevalent form of human cancer, UV radiation is an important environmental carcinogen. The basic objective of the proposal is to investigate the role of cellular oncogenes in UV carcinogenesis. Many cellular oncogenes are known to be associated with a variety of human and rodent tumors. Induction of tumors in rodents by defined chemicals has resulted in frequent activation of specific oncogenes. However, it is not known whether UV radiation activates proto-oncogenes in a carcinogen-specific manner. Therefore, an analysis of UV- induced murine skin cancers for activated oncogenes and a comparison with the oncogenes activated in mouse skin cancers of the same histologic type but induced by different chemical carcinogens will permit experimental evaluation of this hypothesis. If the mechanism of UV-induction of cancer is as specific as chemical-induction of cancer, then an analysis of the presence of transfectable oncogenes in human skin cancers occurring on sun-exposed body sites will reveal whether the same oncogenes are also activated in these tumors. We propose to determine whether skin cancers induced in mice by UV radiation and human skin cancers occurring on sun-exposed body sites contain similar activated oncogenes. The oncogenes will be identified by their ability to induce tumorigenic transformation by DNA-mediated gene transfer into 3 recipient cell systems, NIH 3T3, C3H 10T1/2, and human HOS cells. Ras oncogenes identified by DNA transfection will be analyzed by the oligomer probe technique to determine their mechanism of activation. If non-ras oncogenes are identified by DNA transfection, we will make an attempt to clone the gene in a bacteriophage or cosmid vector. Information obtained from these studies may help to understand the molecular mechanisms of carcinogenesis and may provide a means of applying this information to human skin cancer.