EXPRESSION OF PACE4 IN CHEMICALLY-INDUCED CARCINOMAS IS ASSOCIATED WITH SPINDLE-CELL TUMOR CONVERSION AND INCREASED INVASIVE ABILITY

Gene expression changes associated with the conversion of squamous cel l carcinoma (SCC) to a more advanced malignant spindle cell carcinoma (SPCC) were determined by differential display. Using an animal model of human SCC progression, we provide evidence of increased PACE4 expre ssion in SPCC cell lines and primary tumors induced bg chemical carcin ogenesis protocols, thug implicating this proprotein convertase in the process of tumor progression, Exogenous overexpression of PACES cDNA in mouse SCC cells of lo pr invasive ability resulted in enhanced tumo r cell invasiveness that was absent in parental or mock-transfected SC C cells. In addition, the PACE4-transfected cells acquired the ability to process prostromelysin 3 into its active enzyme form. Taken togeth er, these results show that up-regulation of PACE4 expression is assoc iated with SCC conversion to SPCC and suggests that activation of esse ntial PACE4 substrates, such as the metalloproteinase stromelysin 3, i s required for tumor cell invasion.