Phorbol ester tumour mediated altered expression and regulation of matrix metalloproteinase-2 in a H-ras transformed cell line capable of benign tumour formation

The matrix metalloproteinases (MMPs) are thought to play key roles in tumou r formation and malignant progression. The present study demonstrates alter ations in the regulation of matrix metalloproteinase-2 (MMP-2) expression i n response to the phorbol ester tumour promoter, PMA, in a H-ras transforme d cell line, NR3, which is capable of benign tumour formation. PMA treatmen t of NR3 cells resulted in decreased expression of MMP-2 mRNA levels. Follo wing a lag period, an accompanying change in gelatinolytic activity was als o found. These PMA-mediated alterations in MMP-2 mRNA levels were independe nt of de novo protein synthesis and involved both transcriptional and post- transcriptional events. Most notably, PMA regulates MMP-2 mRNA expression t hrough a mechanism involving message de-stabilization. Additionally, protei n kinase C mediated events were found to play a role(s) in the regulation o f MMP-2 message expression in NR3 cells. This study demonstrates several no vel aspects regarding the regulation of MMP-2 expression in a H-ras transfo rmed cell line and thereby provides further insight into the altered growth regulatory programs associated with H-ras mediated cellular transformation .