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Matrix Metalloproteinase 9 Is a Mediator of Epidermal Growth Factor–Dependent E-Cadherin Loss in Ovarian Carcinoma Cells

¹ Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico; Departments of ² Cell and Molecular Biology and ³ Pathology, Northwestern University Feinberg Medical School, Chicago, Illinois; ⁴ Obstetrics and Gynecology, New York University School of Medicine, New York, New York; ⁵ Pathology and Anatomical Science, University of Missouri School of Medicine, Columbia, Missouri

Requests for reprints: Laurie G. Hudson, MSC09 5360, University of New Mexico, Albuquerque, NM 87131-0001. Phone: 505-272-2482; Fax: 505-272-0704; E-mail: lhudson{at}salud.unm.edu.

Key Words: epidermal growth factor receptor • matrix metalloproteinases • E-cadherin

Epidermal growth factor (EGF) receptor (EGFR) is frequently elevated in epithelial ovarian cancer, and E-cadherin expression is often reduced in advanced disease. In this study, we investigated a mechanism by which EGFR activation promotes disruption of adherens junctions through induction of matrix metalloproteinase 9 (MMP-9). We show that EGFR activation down-modulates E-cadherin, and broad spectrum MMP inhibition ameliorates EGF-stimulated junctional disruption and loss of E-cadherin protein. MMP-9 involvement in EGF-dependent down-regulation of E-cadherin was determined by siRNA specifically directed against MMP-9. Furthermore, treatment with recombinant MMP-9 or transient expression of MMP-9 is sufficient to reduce E-cadherin levels in differentiated ovarian tumor cells. Stable overexpression of MMP-9 led to a loss of E-cadherin and junctional integrity, and promoted a migratory and invasive phenotype. Thus, elevated MMP-9 protein expression is sufficient for junctional disruption and loss of E-cadherin in these cells. The associations between EGFR activation, MMP-9 expression, and E-cadherin were investigated in human ovarian tumors and paired peritoneal metastases wherein immunohistochemical staining for activated (phospho) EGFR and MMP-9 colocalized with regions of reduced E-cadherin. These data suggest that regulation of MMP-9 by EGFR may represent a novel mechanism for down-modulation of E-cadherin in ovarian cancer. [Cancer Res 2008;68(12):4606–13]

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