title: Matrilysin (MMP-7) promotes invasion of ovarian cancer cells by activation of progelatinase.
abstract: Although matrilysin (MMP-7) is overexpressed in various malignancies, few studies have evaluated its role in epithelial ovarian cancer (EOC) invasion and metastasis. We report that the secretion of MMP-7 in EOC is stimulated significantly by vascular endothelial growth factor (VEGF) and interlukin-8 (IL-8). We also examined the in vivo expression of MMP-7 in EOC and its effects on the in vitro invasion and progelatinase activation. We report that MMP-7 is overexpressed in ovarian cancer cell lines and EOC surgical specimens. DOV13 cells incubated with active rhMMP-7 significantly increased cellular invasion and proMMP-2 activation. RhMMP-7 also showed the ability to activate proMMP-2 and proMMP-9 in immortalized ovarian epithelial cell (IOSE-29) conditioned medium. In addition, rhMMP-7 was able to activate progelatinase in a concentration-dependent manner in vitro. TIMP-2 or the generic MMP inhibitor-GM6001 inhibited both the activation of proMMP-2 and the increased invasion of DOV13 cells promoted by rhMMP-7. By incubation of MMP2-TIMP-2 complex with equal molar rhMMP-7, MMP-2 was dissociated from the complex and activated in a time-dependent manner, suggesting that TIMP-2 helps to keep the latency of MMP-2. TIMP-2 also showed inhibitory effects on the MMP-7 induced increase of gelatinolytic activity in DOV13 and IOSE-29 conditioned media. A strong co-localization of MMP-7 and MMP-2 was observed in DOV13 cells and ovarian carcinoma permanent tissue sections. These results indicate MMP-7 is overexpressed in malignant ovarian epithelium and suggest MMP-7 may facilitate tumor cell invasion in vivo partly through the induction of progelatinase activation.
authors.affiliation: Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Feng-Qiang
authors.initials: FQ
authors.lastname: Wang
authors.forename: John
authors.initials: J
authors.lastname: So
authors.forename: Scott
authors.initials: S
authors.lastname: Reierstad
authors.forename: David A
authors.initials: DA
authors.lastname: Fishman
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002277:Carcinoma / Q000201:enzymology* / Q000473:pathology*; D045744:Cell Line, Tumor; D017364:Collagenases / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000187:drug effects / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D018093:Gelatinases / Q000187:drug effects / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D016209:Interleukin-8 / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism* / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000187:drug effects / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology*; D011480:Protease Inhibitors / Q000494:pharmacology; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004151:Dipeptides; D004792:Enzyme Precursors; D016209:Interleukin-8; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D019716:Tissue Inhibitor of Metalloproteinase-2; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; C120487:pro-matrix metalloproteinase 9; C069860:progelatinase; D020783:Matrix Metalloproteinase 7; D020780:Matrix Metalloproteinase 9