Matrix metalloproteinase 9 is a mediator of epidermal growth factor-dependent e-cadherin loss in ovarian carcinoma cells.
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.
Cowden Dahl
Karen D
KD
Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico, USA.
Symowicz
Jaime
J
Ning
Yan
Y
Gutierrez
Elisa
E
Fishman
David A
DA
Adley
Brian P
BP
Stack
M Sharon
MS
Hudson
Laurie G
LG
D022005:Adherens Junctions / Q000502:physiology; D001202:Ascitic Fluid / Q000201:enzymology; D015153:Blotting, Western; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D046888:Tissue Array Analysis; D014162:Transfection
D015820:Cadherins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020780:Matrix Metalloproteinase 9