Posttranscriptional regulation of urokinase receptor gene expression in human lung carcinoma and mesothelioma cells in vitro

The urokinase-type plasminogen activator (uPA) interacts with its receptor (uPAR) to promote proteolysis as well as cell proliferation and migration. These functions contribute to the pathogenesis of neoplastic growth and inv asiveness. Expression of uPAR in tumor extracts also inversely correlates w ith prognosis in many forms of cancer. In this study, we sought to determin e if differences in uPAR expression were distinguishable between cultured h uman lung carcinoma and malignant mesothelioma subtypes. We also sought to determine if, as in malignant mesothelioma cells, uPAR expression is regula ted at the posttranscriptional level in cultured malignant lung carcinoma c ells. Using I-125-uPA binding and ligand blotting techniques, uPAR was expr essed by phenotypically diverse lung carcinoma cell lines, including the H4 60, H157 and H1395 non-small cell lines and the H146 small cell lung carcin oma line. Increased uPAR expression was also detected in spindle-shaped (M3 3K) and epithelioid (M9K and MS-1) malignant mesothelioma cells. Selected m ediators, including TGF-beta, TNF-alpha, LPS and PMA, uniformly enhanced uP AR expression in each of the tumor cell lines. Steady state uPAR mRNA expre ssion was determined by RNase protection assay and correlated directly with the changes in cell surface uPAR expression. By gel mobility shift and UV- cross linking assays, a uPAR mRNA binding protein (uPAR mRNABp) implicated in the posttranscriptional control of message stability, was identified in each of the cell lines. Expression of uPAR and its message in cultured lung carcinoma and malignant mesothelioma cells is similarly influenced by effe ctors present in the tumor microenvironment. Regulation of the uPAR message occurs at the posttranscriptional level in cultured small and non-small ce ll lung carcinoma cells as well as spindle-shaped and fibrous malignant mes othelioma cell lines. Posttranscriptional regulation of uPAR in all these c ells involves the interaction of the uPAR mRNABp with uPAR mRNA, which prom otes uPAR mRNA destabilization.