Matrix metalloproteinase 9 is a mediator of epidermal growth factor-dependent E-cadherin loss in ovarian carcinoma cells

Karen D. Cowden Dahl, Jaime Symowicz, Yan Ning, Elisa Gutierrez, David A. Fishman, Brian P. Adley, M. Sharon Stack, Laurie G. Hudson

Research output: Contribution to journalArticle

117 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4606-4613
Number of pages8
JournalCancer Research
Volume68
Issue number12
DOIs
StatePublished - Jun 15 2008

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Cowden Dahl, K. D., Symowicz, J., Ning, Y., Gutierrez, E., Fishman, D. A., Adley, B. P., Stack, M. S., & Hudson, L. G. (2008). Matrix metalloproteinase 9 is a mediator of epidermal growth factor-dependent E-cadherin loss in ovarian carcinoma cells. Cancer Research, 68(12), 4606-4613. https://doi.org/10.1158/0008-5472.CAN-07-5046