Coordinated expression of the vitronectin receptor and the urokinase-type plasminogen activator receptor in me- tastatic melanoma cells

Integrin avj83 is a marker of progression in malignant mela-noma. Previously we reported that human melanoma cells derived from regional lymph node metastases had increased a483-mediated adhesion to lymph node vitronectin. In the present study, the expression and function of tvf33 were further investigated with emphasis on the functional rela-tionship between a433 and the urokinase-type plasminogen activator system of proteolysis. We found that metastases-derived melanoma MeWo LNI 61 (61) and MIM/8 LNI cells had a markedly increased expression of i,1 mRNA tran-scripts relative to the parent lines which was reflected in significantly elevated levels of the av83 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 plasmino-gen activator as detected by immunolabeling. To determine whether the expression of uPAR and a, were linked, a, synthesis in the metastatic melanoma cells was suppressed using ae antisense phosphorothioate oligonucleotides. This resulted in a marked decrease in detectable ci, 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- 50 % in uPAR mRNA levels: On the other hand, liga-tion of the a413 receptor on the melanoma cells by immobi-lized 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. (J. Clin. Invest. 1995. 95:2096-2103.) Key words: metastasis * melanoma * inte-grin * vitronectin receptor * urokinase plasminogen activa-tor receptor