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Reversion of the Invasive Phenotype of Transformed Human Fibroblasts by Anti-Messenger Oligonucleotide Inhibition of Urokinase Receptor Gene Expression¹

Istituto di Pathologia Generale, Università di Firenze, Viale Morgagni, 50, 50134 Florence, Italy

The receptors for urokinase plasminogen activator were studied in both normal human fibroblasts (WI-38 cells) and their SV40-transformed counterpart (VA-13 cells). We have shown that transformed cells expose 10 times more urokinase plasminogen activator receptors (u-PAR) than normal cells. By cross-linking aliquots of cell lysates with the aminoterminal 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 invade the basement membrane Matrigel. Switching off the receptor gene expression by the anti-messenger oligodeoxynucleotides strategy abolished the invasive properties of transformed cells. The anti-messenger oligodeoxynucleotide sequence we have designed inhibited the u-PAR gene expression, lowering both the receptor and the receptor mRNA. This indicates that overexpression of u-PAR gene is itself responsible for invasivity of transformed fibroblasts in our cell model system and that antisense compound therapy may prove to be of clinical interest in the control of cancer spreading.

¹ Work supported by grants from CNR (P. F. ACRO, Attività di Comitato and Progetto Strategico "Nucleotidi Antisenso come Strumenti di Nuove Strategie Terapeutiche"), MURST (40% and 60%), Ente Cassa di Risparmio di Firenze, and in part by Associazione Italiana per la Ricerca sul Cancro (AIRC). E. A. is the recipient of a fellowship from Accademia Nazionale dei Lincei. A. Q. is the recipient of a fellowship from AIRC.

Received 8/ 2/94. Accepted 10/29/94.

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