THE MELANOMA DIFFERENTIATION-ASSOCIATED GENE MDA-7 SUPPRESSES CANCER CELL-GROWTH

Cancer is a disease characterized by defects in growth control, and tu mor cells often display abnormal patterns of cellular differentiation. The combination of recombinant human fibroblast interferon and the an tileukemic agent mezerein corrects these abnormalities in cultured hum an melanoma cells resulting in irreversible growth arrest and terminal differentiation. Subtraction hybridization identifies a melanoma diff erentiation associated gene (mda-7) with elevated expression in growth arrested and terminally differentiated human melanoma cells, Colony f ormation decreases when mda-7 is transfected into human tumor cells of diverse origin and with multiple genetic defects. In contrast, the ef fects of mda-7 on growth and colony formation in transient transfectio n assays with normal cells, including human mammary epithelial, human skin fibroblast, and rat embryo fibroblast, is quantitatively less tha n that found with cancer cells. Tumor cells expressing elevated mda-7 display suppression in monolayer growth and anchorage independence, In fection 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 (RE) and p53 genes indicates a lack of involvement of these critical tumor supp ressor elements in mediating mda-7-induced growth inhibition, The lack of protein homology of mda-7 with previously described growth suppres sing genes and the differential effect of this gene on normal versus c ancer cells suggests that mda-7 may represent a new class of cancer gr owth suppressing genes with antitumor activity.