S. Shetty et S. Idell, Posttranscriptional regulation of urokinase receptor gene expression in human lung carcinoma and mesothelioma cells in vitro, MOL C BIOCH, 199(1-2), 1999, pp. 189-200
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.