Ets-1 transcription factor-mediated urokinase-type plasminogen activator expression and invasion in glioma cells stimulated by serum and basic fibroblast growth factors

Overexpression of urokinase plasminogen activator (uPA) has been proposed t o be one of the mechanisms by which malignant glioma cells cause pericellul ar proteolysis of stromal structures during brain-tissue invasion. However, knowledge about the mechanisms that regulate uPA in glioma cells is still rather scant. Growth factors, particularly epidermal growth factor and basi c fibroblast growth factor (bFGF), regulate uPA synthesis in Various nongli al cells. Because these factors have been associated with glioma invasion, we thought that perhaps similar events may occur in glioma cells. In this s tudy, we demonstrate that growth factors regulate uPA gene transcription in glioma cells by induction of Ets-l transcription factor. Serum and bFGF tr eatment concomitantly stimulated baseline levels of Ets-l and uPA mRNA and protein, and this was associated with a marked increase in the migration an d invasion potentials of glioma cells in vitro. Treatment of cells with ant isense Ets-l but not the control sense oligonucleotides concurrently inhibi ted the expression of Ets-l and uPA, and this blocked glioma cell migration and invasion by more than 50%. in addition, medium conditioned by antisens e Ets-l oligonucleotide-treated cells showed markedly reduced uPA activity, as determined by casein zymography. These results strongly suggest that se rum and bFGF control glioma invasion by inducing synthesis of Ets-l transcr iption factor, which directly up-regulates expression of uPA in glioma cell s. Antisense inhibition of Ets-l expression may therefore provide a potenti al and exciting therapeutic target for preventing invasion by glioma cells.