Abnormalities in differentiation are common occurrences in human cancers. Treatment of human melanoma cells with combination of recombinant human fibroblast interferon and the protein kinase C activating compound mezerein results in a loss of tumorigenic potential that correlates with an irreversible suppression in proliferative ability and induction of terminal differentiation. It is hypothesized that this process involves the differential expression of genes, which regulate cancer cell growth and differentiation. Through the use of subtraction hybridization, we have 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. Remarkably, when metastatic human melanomas are induced to irreversibly growth arrest, terminally differentiate and lose cancerous properties, mda-7 expression increases dramatically. Ectopic expression of mda-7 using a recombinant adenovirus, Ad.mda-7, results in growth suppression and apoptosis in diverse cancer cell types, including tumor cells with wild-type p53 or mutant for p53, Rb, or p53 + Rb. Moreover, growth and progression of human breast and cervical cancer cells in vivo in nude mice is inhibited by Ad.mda-7. In contrast, no deleterious effect is apparent after infection of normal human epithelial or fibroblast cells with Ad.mda-7. Based on these pre-clinical findings, Phase I Clinical Trials are now being performed to evaluate mda-7 for cancer therapeutic applications. In these contexts, an in-depth mechanistic analysis of this fascinating and potentially significant tumor suppressor molecule is warranted. Selective induction of apoptosis in human breast cancer cells correlates with an elevation in the level of the pro-apoptotic protein BAX and an increase in the ratio of BAX to BCL-2, an inhibitor of apoptosis. The mechanism by which mda-7 modifies cancer progression an suppresses human cancer cell growth will be evaluated with a particular emphasis on its functional relationship to apoptosis. Recent information indicates that mda-7 is a novel member of the IL-10 cytokine gene family. Experiments will focus on defining the functional domains of mda-7 that determine biological activity and identifying biochemical pathways, interacting partners and potential targets or mediators of activity. Studies will also examine the mechanism underlying mda-7's """"""""bystander effect."""""""" These investigations will provide important insights into a novel cancer growth-suppressing 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 neoplastic process, thereby attenuating or eliminating cancer aggressiveness and metastasis. Understanding the mode of action of mda-7 will promote translational applications for cancer therapy.
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