Urokinase activity in corneal fibroblasts may be modulated by DNA damage and secreted proteins

Proteases like urokinase-type plasminogen activator (uPA) play an important role in tumor invasion. Cells derived from ultraviolet radiation (UVR)-ind uced corneal sarcomas of Monodelphis domestica produce relatively. high lev els of uPA compared to the untransformed keratocytes suggesting a mechanism for their invasiveness. Because UVR is known to stimulate uPA production i n many cell types, UVR exposure may further increase uPA expression in corn eal tumor tells, thus enhancing their ability to infiltrate. We investigate d control of basal uPA levels and the induction of uPA by UVR in transforme d and untransformed corneal keratocytes from Monodelphis. These studies too k advantage of the fact that Monodelphis possesses an active photolyase tha t can be stimulated to remove UVR-induced pyrimidine dimers by exposure to long-wavelength visible photoreactivating light (PRL), Our studies showed t hat significant induction of uPA occurred in response to 200 J/m(2) UVR, Th is induction was partially blocked by treatment with PRL, indicating that D NA damage, the pyrimidine dimer in particular, played a role in uPA inducti on. in untransformed cultured corneal fibroblasts, the heparin-binding prot ein inhibitor, suramin, reduced basal uPA levels, UVR-induced uPA productio n and cell proliferation. Basic fibroblast growth factor, a heparin-binding growth factor known to be UVR-inducible in mesenchymal cells, stimulated u PA production and cell proliferation; however, anti-bFGF antibodies did not significantly decrease proliferation or basal uPA production. These findin gs suggested that basal levels of uPA secretion were modulated in response to heparin-binding growth factors and that these growth factors may also ha ve mediated the effect of UVR on uPA levels.