Cancer is a progressive multigenic disorder characterized by defined changes in the transformed phenotype that culminates in metastatic disease. Although an area of intense investigation, the important mediators of cancer progression, remain enigmas. Determining the molecular basis of progression should lead to new opportunities for improved diagnostic and therapeutic modalities. Human melanoma cells can be induced to revert to a more normal phenotype and lose proliferative capacity irreversibly and terminally differentiate by treatment with recombinant human fibroblast interferon and mezerein. This model system is permitting a detailed molecular analysis of the genes regulated during and controlling cell growth, differentiation and the cancer phenotype. Through the use of subtraction hybridization, the investigator has identified a gene associated with induction of irreversible growth arrest, cancer reversion and terminal differentiation in human melanoma cells, melanoma differentiation associated gene-7 (mda-7). mda-7 is a novel gene that displays reduced expression in metastatic human melanoma versus normal human melanocytes. Strikingly, when metastatic human melanomas are induced to irreversibly growth arrest, terminally differentiate and lose cancerous properties, mda-7 expression increases dramatically. Immunofluorescence studies indicate that mda-7 localizes to the nucleus during cellular differentiation and growth arrest and interacts with chromatin during cellular mitosis. Ectopic expression of mda-7 results in apoptosis in diverse cancer cell types, including tumor cells with wild-type p53 or mutant for p53, Rb or p53 + Rb, but not in normal human epithelial and fibroblast cells. The mechanism by which mda-7 modifies progression and suppresses human cancer cell growth will be evaluated with a particular emphasis on its functional relationship to cellular senescence and apoptosis. These cell culture studies will make use of expression constructs and recombinant adenoviruses to xpress sense and antisense mda-7. To define the role of mda-7 in vivo, tissue and generalized gene knockouts of mda-7 will be constructed by homologous recombination. These investigations will provide important insights into a novel cancer progression gene with potential relevance to a broad spectrum of human cancers. As such, this gene may serve as a target for selectively intervening in the progression process, thereby attenuating or eliminating cancer aggressiveness and metastasis.
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