GENES INVOLVED IN PRENEOPLASTIC PROGRESSION

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The aim of this research is to identify and characterize two classes of genes involved in multistage carcinogenesis. The first class includes genes associated with susceptibility to tumor promoter-induced neoplastic transformation. The second class includes genes that specify expression of tumor cell phenotype. Mouse JB6 promotion-resistant (P-), promotion- sensitive (P+), and tumorigenic (Tx) JB6-derived epidermal cell lines have been found to differ in the expression of several genes described in the accompanying project Z01CP05383-09 LVC, "Membrane Signal Transduction in Tumor Promotion." The changes in expression of these genes during the progression from P- to P+ to Tx phenotypes appear to be genetically controlled in these stable variant cell lines. We have recently discovered a stable change in a response to tumor promoters by a JB6- derived tumorigenic cell line. The change involves acquisition of a cell- killing response to activators of protein kinase C. The treated cells show the non-random DNA damage that characterizes apoptosis (programmed cell death), a finding of significance for cancer treatment. A novel transformation-associated sequence unrelated to any known oncogene has been cloned from human nasopharyngeal carcinoma (NPC) cells by human Alu screening of an NPC/JB6 transfectant genomic library. A recently isolated homologous NPC cDNA clone encodes, in part, immunoglobulin kappa. In addition, NPC cell lines and a biopsy show the same expressed mutation in one of the "hot spots" of the tumor suppressor gene p53. New evidence shows that the novel mutated p53 has oncogenic activity. Additional NPC samples from Alaskan patients are being provided to us for examination of both the newly cloned NPC transformation-associated gene and the p53 gene for transformation-relevant mutations. Finally, we have learned that JB6 P+ cells can be transformed to a tumor phenotype by overexpression of activated v-H-ras, v-raf, or src, but not by any of several other oncogenes. The profiles of gene expression in these JB6/oncogene transfectant cell lines are being examined to increase our understanding of transformation pathways in the JB6 model.