The invasive behavior of oral carcinoma requires coordinated cellular events including basement membrane attachment and detachment, extracellular matrix (ECM) proteolysis, and acquisition of motility. Altered expression of matrix binding integrins is associated with oral carcinoma progression. Integrins can promote an hierarchy of cellular responses dictated by the physical nature of the integrin engagement, thereby transducing distinct signals from the ECM. Production of two distinct classes of ECM-degrading proteinases, plasminogen activators (PA) and matrix metalloproteinases (MMP) is also in early event in malignant progression. The correlation between enhanced expression of the serine proteinase urinary-type PA (uPA or urokinase), MMP-9 (gelatinase B) and tumor progression is well described. Binding of urinary type-PA (uPA) o its cellular receptor (uPAR) leads to enhanced pericellular plasmin formation, which in turn directly degrades ECIV giycoproteins and activates selected MMPs such as MMP-9. Moreover, uPAJR may also regulate invasive behavior via novel, proteinase-independent mechanisms, by modifying integrin adhesive functions and modulating integrin signaling pathways. Our data demonstrate that a3b1 integrin aggregation alters expression of both uPA and MMP-9. Further, a3bl integrin aggregation induces uPA/R/a3b 1 integrin association and MAP kinase (MAPK) activation, resulting in enhance( proteinase transcription Based on these results, it is the working hypothesis of this proposal that a functional link between adhesion and proteolysis regulates oral carcinoma invasive behavior. Specifically we propose a multi-functional interaction of the uPA/R system with carcinoma cell integrins, such that integrin-in edited adhesion modulates cellular, iPA expression, while subsequent uPA/uPAR/integrin interactions in turn regulate downstream adhesive events that control proteinase expression, proliferation, adhesion and motility. To test this hypothesis, we will assess the specific physical parameters of a3b1 integrin engagement that control proteinase induction. The ability of uPAIR to modulate a3b1 signaling and modify proteinase expression and proliferation will then be analyzed. Immunohistochemical and biochemical analysis of normal and tumor tissues will be employed to evaluate integrin, proteinase, and MAPK expression and activity. The functional contribution of induced proteinases to the cellular invasive phenotype will then be evaluated. The long term goal of the proposed research is to provide a more detailed understanding of the functional link between adhesion and proteolysis and the con tribution of this in terplay to regulation of metastasis.
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