TRANSCRIPTIONAL ACTIVATION OF THE UROKINASE RECEPTOR GENE IN INVASIVECOLON-CANCER

The plasminogen activator urokinase promotes tumor invasion by convert ing plasminogen into plasmin, which degrades several extracellular mat rix components. Urokinase can bind to a specific cell surface receptor , which leads to accelerated plasmin production. While there is good e vidence indicating a role for this binding site in tumor invasion/meta stasis, there is little information concerning the regulation of uroki nase receptor expression in invasive cancer. To address this question a series of colon cancer cell lines, which demonstrate either a high o r low ability to invade an extracellular matrix-coated porous filter, was characterized for receptor expression at the transcriptional and p ost-transcriptional revels. The invasive cell lines possessed In-fold more receptors than their non-invasive counterparts as shown by cross- linking experiments and by Western blotting. Northern blotting indicat ed that this disparity in receptor number could be largely accounted f or by a different amount of steady-state mRNA encoding the binding sit e. However, neither gene amplification nor enhanced mRNA stability cou ld account for the augmented receptor protein observed for the invasiv e colon cancer cell types. In contrast, nuclear run-on experiments wit h representative cell lines revealed that the 10-fold difference in re ceptor display between the invasive-competent and invasive-deficient c ells could be largely accounted for by differences in transcription ra tes. Transcription of the u-PAR gene in the receptor-deficient GEO cel ls, but not in the receptor-rich RKO cells, could be augmented by prot ein kinase C stimulation. These findings provide a clear rationale for studies to determine if the urokinase receptor promoter in invasive c olon cancer is activated in cis or in frons. (C) 1994 Wiley-Liss, Inc.