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The melanoma differentiation associated gene mda-7 suppresses cancer cell growth
1Department of Pathology, Columbia-Presbyterian Cancer Center, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
Abstract:
Cancer is a disease characterized by defects in growth control, and tumor cells often display abnormal patterns of cellular differentiation. The combination of recombinant human fibroblast interferon and the antileukemic agent mezerein corrects these abnormalities in cultured human melanoma cells resulting in irreversible growth arrest and terminal differentiation. Subtraction hybridization identifies a melanoma differentiation associated gene (mda-7) with elevated expression in growth arrested and terminally differentiated human melanoma cells. Colony formation decreases when mda-7 is transfected into human tumor cells of diverse origin and with multiple genetic defects. In contrast, the effects of mda-7 on growth and colony formation in transient transfection assays with normal cells, including human mammary epithelial, human skin fibroblast, and rat embryo fibroblast, is quantitatively less than that found with cancer cells. Tumor cells expressing elevated mda-7 display suppression in monolayer growth and anchorage independence. Infection with a recombinant type 5 adenovirus expressing antisense mda-7 eliminates mda-7 suppression of the in vitro growth and transformed phenotype. The ability of mda-7 to suppress growth in cancer cells not expressing or containing defects in both the retinoblastoma (RB) and p53 genes indicates a lack of involvement of these critical tumor suppressor elements in mediating mda-7-induced growth inhibition. The lack of protein homology of mda-7 with previously described growth suppressing genes and the differential effect of this gene on normal versus cancer cells suggests that mda-7 may represent a new class of cancer growth suppressing genes with antitumor activity.
Insights
A novel gene, melanoma differentiation associated gene-7 (mda-7), effectively halts cancer cell growth and differentiation. This gene shows potent antitumor activity, particularly in cancer cells, and may represent a new class of cancer-fighting genes.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Cancer is characterized by uncontrolled growth and abnormal cellular differentiation.
- Melanoma cells exhibit these defects, making them a focus for therapeutic research.
Purpose of the Study:
- To identify genes involved in melanoma cell differentiation and growth arrest.
- To investigate the potential of a newly identified gene, mda-7, as a cancer growth suppressor.
Main Methods:
- Subtraction hybridization to identify differentially expressed genes.
- Transfection assays to assess the functional role of mda-7 in various cancer and normal cells.
- Adenovirus-mediated gene expression to study mda-7's effects in vivo.
Main Results:
- mda-7 expression is elevated in growth-arrested and terminally differentiated melanoma cells.
- mda-7 transfection suppresses colony formation and monolayer growth in diverse cancer cells.
- mda-7's growth-suppressing effects are significantly greater in cancer cells than in normal cells.
- Antisense mda-7 reverses growth suppression, confirming its role.
- mda-7 inhibits growth independently of retinoblastoma (RB) and p53 tumor suppressor genes.
Conclusions:
- mda-7 is a novel gene that induces growth arrest and terminal differentiation in cancer cells.
- mda-7 exhibits potent antitumor activity with differential effects on cancer versus normal cells.
- mda-7 represents a new class of cancer growth-suppressing genes with potential therapeutic applications.