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 melanoma, Previously we reported that human melanoma cells derived from regional lymph node metastases had increased alpha(x) beta(3)-mediated adhesion to lymph node vitronectin. In the present study, the expression and function of alpha(v) beta(3) were further investigated with emphasis on the functional relationship between alpha(v) beta(3) and the urokinase-type plasminogen activator system of proteolysis, We found that metastases-derived melanoma MeWo LNI 6I (6I) and MIM/8 LNI cells had a markedly increased expression of alpha(v) mRNA transcripts relative to the parent lines which was reflected in significantly elevated levels of the alpha(v) beta(3) heterodimers on the cell surface, These cells 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 whether the expression of uPAR and alpha(v) were linked, alpha(v) synthesis in the metastatic melanoma cells was suppressed using alpha(v) antisense phosphorothioate oligonucleotides. This resulted in a marked decrease in detectable alpha(v), mRNA and protein and a corresponding substratum-specific reduction in cell adhesion to vitronectin. When uPAR expression in these cells was subsequently analyzed, we found a reduction 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 suggest that the expression of uPAR in metastatic melanoma cells is linked to the expression and function of the vitronectin receptor.