Transcriptional activation of the urokinase receptor gene in invasive colon cancer.
The plasminogen activator urokinase promotes tumor invasion by converting plasminogen into plasmin, which degrades several extracellular matrix components. Urokinase can bind to a specific cell surface receptor, which leads to accelerated plasmin production. While there is good evidence indicating a role for this binding site in tumor invasion/metastasis, there is little information concerning the regulation of urokinase receptor expression in invasive cancer. To address this question a series of colon cancer cell lines, which demonstrate either a high or low ability to invade an extracellular matrix-coated porous filter, was characterized for receptor expression at the transcriptional and post-transcriptional levels. The invasive cell lines possessed 10-fold more receptors than their non-invasive counterparts as shown by cross-linking experiments and by Western blotting. Northern blotting indicated that this disparity in receptor number could be largely accounted for by a different amount of steady-state mRNA encoding the binding site. However, neither gene amplification nor enhanced mRNA stability could account for the augmented receptor protein observed for the invasive colon cancer cell types. In contrast, nuclear run-on experiments with representative cell lines revealed that the 10-fold difference in receptor display between the invasive-competent and invasive-deficient cells could be largely accounted for by differences in transcription rates. Transcription of the u-PAR gene in the receptor-deficient GEO cells, but not in the receptor-rich RKO cells, could be augmented by protein kinase C stimulation. These findings provide a clear rationale for studies to determine if the urokinase receptor promoter in invasive colon cancer is activated in cis or in trans.
Wang
H
H
Department of Tumor Biology, M.D. Anderson Cancer Center, Houston, TX 77030.
Skibber
J
J
Juarez
J
J
Boyd
D
D
D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005796:Genes; D006801:Humans; D009361:Neoplasm Invasiveness; D010703:Phorbol Esters / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics*; D055293:Receptors, Urokinase Plasminogen Activator; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
C524898:PLAUR protein, human; D010703:Phorbol Esters; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator