COORDINATED EXPRESSION OF THE VITRONECTIN RECEPTOR AND THE UROKINASE-TYPE PLASMINOGEN-ACTIVATOR RECEPTOR IN METASTATIC MELANOMA-CELLS

Integrin alpha(v) beta(3) is a marker of progression in malignant mela noma, Previously we reported that human melanoma cells derived from re gional lymph node metastases had increased alpha(x) beta(3)-mediated a dhesion to lymph node vitronectin. In the present study, the expressio n and function of alpha(v) beta(3) were further investigated with emph asis on the functional relationship between alpha(v) beta(3) and the u rokinase-type plasminogen activator system of proteolysis, We found th at metastases-derived melanoma MeWo LNI 6I (6I) and MIM/8 LNI cells ha d a markedly increased expression of alpha(v) mRNA transcripts relativ e to the parent lines which was reflected in significantly elevated le vels of the alpha(v) beta(3) heterodimers on the cell surface, These c ells also expressed elevated levels of urokinase plasminogen activator receptor (uPAR) mRNA and had higher levels of surface bound urokinase plasminogen activator as detected by immunolabeling. To determine whe ther the expression of uPAR and alpha(v) were linked, alpha(v) synthes is in the metastatic melanoma cells was suppressed using alpha(v) anti sense phosphorothioate oligonucleotides. This resulted in a marked dec rease in detectable alpha(v), mRNA and protein and a corresponding sub stratum-specific reduction in cell adhesion to vitronectin. When uPAR expression in these cells was subsequently analyzed, we found a reduct ion of similar to 50% in uPAR mRNA levels. On the other hand, ligation of the alpha(v) beta(3) receptor on the melanoma cells by immobilized antibody resulted in a twofold increase in uPAR mRNA, The results sug gest that the expression of uPAR in metastatic melanoma cells is linke d to the expression and function of the vitronectin receptor.