Inhibition of Matrilysin Expression by Antisense or RNA Interference Decreases Lysophosphatidic Acid–Induced Epithelial Ovarian Cancer Invasion

Abstract

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 Mmol/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. (Mol Cancer Res 2006;4(11):831 -41)

The Inflammatory Kinase MAP4K4 Promotes Reactivation of Kaposi's Sarcoma Herpesvirus and Enhances the Invasiveness of Infected Endothelial Cells

“…COX-2 is a known mediator of angiogenesis and tumour cell invasiveness, as it leads to production of inflammatory cytokines, growth factors, angiogenic factors, and MMPs in various tumours, as well as in KSHV infected cells [20], [77], [116]–[122]. We could also show that, similarly to MAP4K4 knockdown, COX-2 silencing or chemical inhibition significantly reduces the invasiveness of KSHV-infected endothelial cells ( figure 6A, 6C ).…”

Clinical utility of circulating matrix metalloproteinase-7 (MMP-7), CC chemokine ligand 18 (CCL18) and CC chemokine ligand 11 (CCL11) as markers for diagnosis of epithelial ovarian cancer

“…In vitro studies show that MMP-7 expression correlated with EOC invasiveness and that lysophosphatidic acid induced EOC invasion through the secretion/activation of MMP-7 [17]. Modification of non-ECM proteins, such as insulin-like growth factor binding proteins, heparin-binding epidermal growth factor precursor and E-cadherin, by MMP-7 is one of the mechanisms by which MMP-7 plays a role in tumorigenesis [reviewed in reference 14].…”

“…Overexpression of tissue MMP-7 was seen in many malignancies such as prostate, stomach, colorectal, lung, esophageal, liver, pancreas, skin, breast, head and neck [reviewed in reference 14]. Previous studies showed that MMP-7 was overexpressed in EOC surgical specimens and ovarian cancer cell lines [15][16][17].…”

Lysophosphatidic acid stimulates cell migration, invasion, and colony formation as well as tumorigenesis/metastasis of mouse ovarian cancer in immunocompetent mice

“…LPA Stimulated Migration of ID8 and SKOV3 Cells via cPLA 2 -, COX-1-, and 15-LOX-Dependent Pathways Similar to human EOC cells (24,(35)(36)(37)(38)(39)(40), LPA (1 μmol/L) induced migration of ID8 cells toward four different extracellular matrix proteins: collagen I, fibronectin, laminin, and vitronectin ( Supplementary Fig. S1A).…”