Inhibition of matrilysin expression by antisense or RNA interference decreases lysophosphatidic acid-induced epithelial ovarian cancer invasion.
Our previous reports show that matrilysin [matrix metalloproteinase (MMP)-7] is overexpressed in epithelial ovarian cancer (EOC) and recombinant MMP-7 promotes EOC invasion in vitro. In the present study, we further evaluated the correlation of MMP-7 expression to EOC invasiveness and examined its role in lysophosphatidic acid (LPA)-induced invasion. By sense and antisense gene transfection in vitro, we show that overexpression of MMP-7 in all MMP-7 stably transfected DOV13 clones significantly enhanced their invasiveness, although MMP-7 antisense transfection caused a 91% decrease of MMP-7 expression (P < 0.01) and 87% decrease of invasion (P < 0.05) in geneticin (G418)-selected DOV13 clone P47-M7As-3 compared with vector-transfected control. As assessed by MMP-7 ELISA, LPA treatment at 10 to 80 micromol/L significantly stimulated the secretion of total MMP-7 in DOV13 conditioned medium (P < 0.01). In addition, LPA apparently induced the activation of MMP-7 in DOV13 cells as detected by gelatin zymography. In the antisense MMP-7-transfected DOV13 clone (P47-M7As-3), LPA-increased invasion was significantly decreased compared with vector control. Moreover, knocking down of MMP-7 by small interfering RNA also suppressed LPA-induced invasion in two EOC cell lines (DOV13 and R182). Altogether, our results show that MMP-7 expression is correlated with EOC invasiveness and LPA-induced MMP-7 secretion/activation may represent a new mechanism that facilitates ovarian cancer invasion besides the well-known induction of MT1-MMP-mediated proMMP-2 activation by LPA.
Wang
Feng-Qiang
FQ
Department of Obstetrics and Gynecology, New York University School of Medicine, 550 First Avenue, TH528, New York, NY 10016, USA. wangf03@med.nyu.edu
Smicun
Yoel
Y
Calluzzo
Nicholas
N
Fishman
David A
DA
D002277:Carcinoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D005260:Female; D006801:Humans; D008246:Lysophospholipids / Q000633:toxicity; D020783:Matrix Metalloproteinase 7 / Q000187:drug effects / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists; D014407:Tumor Cells, Cultured
D008246:Lysophospholipids; D061965:Matrix Metalloproteinase Inhibitors; D034741:RNA, Small Interfering; D049368:Receptors, Lysophosphatidic Acid; D020783:Matrix Metalloproteinase 7; C032881:lysophosphatidic acid