During the process of multistage carcinogenesis, the progression of target cells through an initiated to premalignant to a malignant state is accompanied by a number of morphological and biochemical changes. These phenotypic changes result from qualitative and quantitative changes in cellular gene products. An understanding of the role of cellular gene (including oncogene) activation in tumor progression could aid us in terms of diagnosis, prevention and treatment of human cancer. The unique model of mouse skin tumor progression in which there are defined, intermediate stages and lesions will be used in the proposed studies. In the previous granting period we identified seven different cellular genes (mal 1-6 and transin) that were overexpressed during mouse skin tumor progression. Presently it is known that mal 1 has a high degree of sequence similarity with beta-actin, and transin codes for a secreted protease with sequence similarity to stromelysin. Part of the proposed work will involve molecular characterization of the mal 1, 2 and 3 genes. To determine whether the mal or transin genes play a functional role in skin tumor progression, the mal 4 and transin genes will be overexpressed in precursor epidermal cells using either plasmid or defective retroviral vectors, and mal 1, 2, 3 and transin overexpression will be blocked in appropriate tumor producing epidermal cells using antisense vectors. For those genes where there is evidence for their functional role in tumor progression, we have proposed to determine the molecular mechanism whereby the genes are overexpressed. To compliment the studies related to overexpression of genes during tumor progression, we plan to identify and c}one gene(s) that can result in the transition of benign papillomas to malignant squamous cell carcinomas by carrying out DNA transfection. Finally, we propose to extend the gene expression studies to human models of skin tumor progression by isolating human cDNA clones homologous to mal and transin genes. These human cDNA probes would be used to study the expression pattern of these genes using in situ hybridization technique during: 1) the progression of actinic keratosis to squamous cell carcinoma, 2) the progression of dysplastic nevi to malignant melanoma.
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