REVERSION OF THE INVASIVE PHENOTYPE OF TRANSFORMED HUMAN FIBROBLASTS BY ANTI-MESSENGER OLIGONUCLEOTIDE INHIBITION OF UROKINASE RECEPTOR GENE-EXPRESSION

The receptors for urokinase plasminogen activator were studied in both normal human fibroblasts (WI-38 cells) and their SV40-transformed cou nterpart (VA-13 cells), We have shown that transformed cells expose 10 times more urokinase plasminogen activator receptors (u-PAR) than nor mal cells, By cross-linking aliquots of cell lysates with the aminoter minal fragment of the A chain of u-PA, containing the receptor-binding sequence, we have observed a u-PAR concentration at focal contacts in both cell lines. Only transformed cells were able to efficiently inva de the basement membrane Matrigel. Switching off the receptor gene exp ression by the anti-messenger oligodeoxynucleotides strategy abolished the invasive properties of transformed cells, The anti-messenger olig odeoxynucleotide sequence we have designed inhibited the u-PAR gene ex pression, lowering both the receptor and the receptor mRNA, This indic ates that overexpression of u-PAR gene is itself responsible for invas ivity of transformed fibroblasts in our cell model system and that ant isense compound therapy may prove to be of clinical interest in the co ntrol of cancer spreading.