title: MMP-1-PAR1 axis mediates LPA-induced epithelial ovarian cancer (EOC) invasion.
abstract: OBJECTIVE
  MMP-1 is over-expressed in many cancers, with high expression often associated with poor survival. In the present study, we examined the expression of MMP-1 in EOC and its role in EOC invasion. Moreover, we evaluated the role of a newly identified MMP-1-protease activated receptor (PAR)-1 axis in LPA-induced EOC invasion.
  
  
  METHODS
  MMP-1 and PAR1 mRNA expression in EOC cell lines was determined by real time PCR. MMP-1 mRNA expression in 96 normal and carcinoma ovarian tissue specimens was analyzed using a TissueScan real time PCR array. MMP-1 concentration in conditioned medium was measured by MMP-1 ELISA. PAR1 protein expression was detected by Western blotting. Cell invasion was evaluated by in vitro Matrigel invasion assay.
  
  
  RESULTS
  In ovarian tumor tissues more MMP-1 expression was observed than in normal ovarian tissues (p<0.05), and its expression correlated with tumor grade (grade 3>grade 2>grade 1). Human recombinant MMP-1 as well as serum free conditioned medium containing high levels of MMP-1 from DOV13 and R182 cells significantly promoted DOV13 cell invasion (p<0.05), implicating a direct role of MMP-1 in EOC invasion. Moreover, MMP-1 induced DOV13 invasion was significantly blocked by PAR1 siRNA silencing. Furthermore, MMP-1 and PAR1 were both significantly induced by LPA (20 μM), and siRNA silencing of MMP-1 and PAR1 both significantly reduced LPA's invasion-promoting effect in DOV13 cells (p<0.05).
  
  
  CONCLUSIONS
  Our results suggest that the MMP-1-PAR1 axis is involved in EOC invasion and at least partially mediates LPA-induced EOC invasion. Therefore, blocking MMP-1 or PAR1 may represent a new therapeutic option for metastatic EOC.
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Feng-qiang
authors.initials: FQ
authors.lastname: Wang
authors.forename: Jessica
authors.initials: J
authors.lastname: Fisher
authors.forename: David A
authors.initials: DA
authors.lastname: Fishman
mesh_terms: D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D009361:Neoplasm Invasiveness; D009375:Neoplasms, Glandular and Epithelial / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014162:Transfection
chemical_list: D008246:Lysophospholipids; D061965:Matrix Metalloproteinase Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D020781:Matrix Metalloproteinase 1; C032881:lysophosphatidic acid