REGULATION OF UROKINASE-TYPE PLASMINOGEN-ACTIVATOR EXPRESSION IN SQUAMOUS-CELL CARCINOMA OF THE ORAL CAVITY

We undertook a study to determine the role and regulation of expressio n of urokinase-type plasminogen activator in squamous-cell carcinoma o f the oral cavity. The contribution of urokinase to the invasive proce ss was clearly demonstrated in experiments in which in vitro invasion by a cultured squamous-cell carcinoma cell line was substantially redu ced by a monoclonal antibody directed at the catalytic site of urokina se. The conditioned medium from 2 invasive cell lines contained high l evels of urokinase. Examination of resected tumors for urokinase revea led (a) localization of the antigen to the tumor cells and (b) higher levels of the plasminogen activator in tumor tissue than in adjacent n on-malignant tissue. These results suggested that elevated expression of urokinase is a common feature of this malignancy. The mRNA half-liv es of cell lines expressing high and low levels of urokinase were simi lar, indicating that elevated levels of mRNA for the plasminogen activ ator were not a consequence of a more stable transcript. No evidence o f u-PA gene amplification was obtained by Southern blotting of DNA der ived from the cell lines expressing high urokinase levels. Transfectio n of squamous-cell carcinoma cells, which express high levels of uroki nase, with a construct bearing the chloramphenicol acetyl transferase gene driven by the full-length (2345 bp) urokinase promoter indicated activation of the urokinase promoter in trans. In conclusion, our resu lts suggest that transcriptional activation of the urokinase gene, in squamous-cell carcinomas of the oral cavity, leads to elevated levels of urokinase mRNA/protein which, in turn, can promote the invasive phe notype.