PEA3 is necessary for optimal epidermal growth factor receptor-stimulated matrix metalloproteinase expression and invasion of ovarian tumor cells

Karen Cowden Dahl, Reema Zeineldin, Laurie G. Hudson

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Elevated expression of the epidermal growth factor (EGF) receptor (EGFR) is detected in human ovarian tumors and is associated with decreased recurrence-free and overall survival. EGFR activation affects tumor progression in part by promoting tumor invasion through the induction of prometastatic matrix metalloproteinases (MMP). PEA3, an ETS family transcription factor, is elevated in advanced and metastatic ovarian cancer and regulates MMPs in various cell types, therefore, we investigated whether PEA3 is required for the EGFR-dependent induction of MMP mRNA. MMP-9 and MMP-14 mRNA levels were selectively increased in response to EGFR activity in ovarian tumor cells. EGFR activation resulted in nuclear accumulation of PEA3 and direct binding of PEA3, but not the related protein ETS-1, to the endogenous MMP-9 and MMP-14 promoters. Furthermore, PEA3 overexpression was sufficient to induce MMP-9 and MMP-14 mRNA, tumor cell migration, and invasion, suggesting that PEA3 is an important contributor to the metastatic phenotype. Additionally, inhibition of PEA3 expression via short interfering RNA reduced the EGF induction of MMP-9 and MMP-14 gene expression by 92% and 50%, respectively, and impaired EGF-stimulated tumor cell invasion. These results suggest that PEA3 is regulated by EGFR and that the elevated PEA3 expression detected in human ovarian cancer may divert cells to a more invasive phenotype by regulating MMP-9 and MMP-14.

Original languageEnglish (US)
Pages (from-to)413-421
Number of pages9
JournalMolecular Cancer Research
Volume5
Issue number5
DOIs
StatePublished - May 2007
Externally publishedYes

Fingerprint

Matrix Metalloproteinase 14
Matrix Metalloproteinases
Epidermal Growth Factor Receptor
Matrix Metalloproteinase 9
Neoplasms
Epidermal Growth Factor
Ovarian Neoplasms
Messenger RNA
Phenotype
Small Interfering RNA
Cell Movement
Transcription Factors
Gene Expression
Recurrence
Survival
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

PEA3 is necessary for optimal epidermal growth factor receptor-stimulated matrix metalloproteinase expression and invasion of ovarian tumor cells. / Cowden Dahl, Karen; Zeineldin, Reema; Hudson, Laurie G.

In: Molecular Cancer Research, Vol. 5, No. 5, 05.2007, p. 413-421.

Research output: Contribution to journalArticle

@article{68f7a2da6d5742b5b5d8b7fe85e68b4f,
title = "PEA3 is necessary for optimal epidermal growth factor receptor-stimulated matrix metalloproteinase expression and invasion of ovarian tumor cells",
abstract = "Elevated expression of the epidermal growth factor (EGF) receptor (EGFR) is detected in human ovarian tumors and is associated with decreased recurrence-free and overall survival. EGFR activation affects tumor progression in part by promoting tumor invasion through the induction of prometastatic matrix metalloproteinases (MMP). PEA3, an ETS family transcription factor, is elevated in advanced and metastatic ovarian cancer and regulates MMPs in various cell types, therefore, we investigated whether PEA3 is required for the EGFR-dependent induction of MMP mRNA. MMP-9 and MMP-14 mRNA levels were selectively increased in response to EGFR activity in ovarian tumor cells. EGFR activation resulted in nuclear accumulation of PEA3 and direct binding of PEA3, but not the related protein ETS-1, to the endogenous MMP-9 and MMP-14 promoters. Furthermore, PEA3 overexpression was sufficient to induce MMP-9 and MMP-14 mRNA, tumor cell migration, and invasion, suggesting that PEA3 is an important contributor to the metastatic phenotype. Additionally, inhibition of PEA3 expression via short interfering RNA reduced the EGF induction of MMP-9 and MMP-14 gene expression by 92{\%} and 50{\%}, respectively, and impaired EGF-stimulated tumor cell invasion. These results suggest that PEA3 is regulated by EGFR and that the elevated PEA3 expression detected in human ovarian cancer may divert cells to a more invasive phenotype by regulating MMP-9 and MMP-14.",
author = "{Cowden Dahl}, Karen and Reema Zeineldin and Hudson, {Laurie G.}",
year = "2007",
month = "5",
doi = "10.1158/1541-7786.MCR-07-0019",
language = "English (US)",
volume = "5",
pages = "413--421",
journal = "Molecular Cancer Research",
issn = "1541-7786",
publisher = "American Association for Cancer Research Inc.",
number = "5",

}

TY - JOUR

T1 - PEA3 is necessary for optimal epidermal growth factor receptor-stimulated matrix metalloproteinase expression and invasion of ovarian tumor cells

AU - Cowden Dahl, Karen

AU - Zeineldin, Reema

AU - Hudson, Laurie G.

PY - 2007/5

Y1 - 2007/5

N2 - Elevated expression of the epidermal growth factor (EGF) receptor (EGFR) is detected in human ovarian tumors and is associated with decreased recurrence-free and overall survival. EGFR activation affects tumor progression in part by promoting tumor invasion through the induction of prometastatic matrix metalloproteinases (MMP). PEA3, an ETS family transcription factor, is elevated in advanced and metastatic ovarian cancer and regulates MMPs in various cell types, therefore, we investigated whether PEA3 is required for the EGFR-dependent induction of MMP mRNA. MMP-9 and MMP-14 mRNA levels were selectively increased in response to EGFR activity in ovarian tumor cells. EGFR activation resulted in nuclear accumulation of PEA3 and direct binding of PEA3, but not the related protein ETS-1, to the endogenous MMP-9 and MMP-14 promoters. Furthermore, PEA3 overexpression was sufficient to induce MMP-9 and MMP-14 mRNA, tumor cell migration, and invasion, suggesting that PEA3 is an important contributor to the metastatic phenotype. Additionally, inhibition of PEA3 expression via short interfering RNA reduced the EGF induction of MMP-9 and MMP-14 gene expression by 92% and 50%, respectively, and impaired EGF-stimulated tumor cell invasion. These results suggest that PEA3 is regulated by EGFR and that the elevated PEA3 expression detected in human ovarian cancer may divert cells to a more invasive phenotype by regulating MMP-9 and MMP-14.

AB - Elevated expression of the epidermal growth factor (EGF) receptor (EGFR) is detected in human ovarian tumors and is associated with decreased recurrence-free and overall survival. EGFR activation affects tumor progression in part by promoting tumor invasion through the induction of prometastatic matrix metalloproteinases (MMP). PEA3, an ETS family transcription factor, is elevated in advanced and metastatic ovarian cancer and regulates MMPs in various cell types, therefore, we investigated whether PEA3 is required for the EGFR-dependent induction of MMP mRNA. MMP-9 and MMP-14 mRNA levels were selectively increased in response to EGFR activity in ovarian tumor cells. EGFR activation resulted in nuclear accumulation of PEA3 and direct binding of PEA3, but not the related protein ETS-1, to the endogenous MMP-9 and MMP-14 promoters. Furthermore, PEA3 overexpression was sufficient to induce MMP-9 and MMP-14 mRNA, tumor cell migration, and invasion, suggesting that PEA3 is an important contributor to the metastatic phenotype. Additionally, inhibition of PEA3 expression via short interfering RNA reduced the EGF induction of MMP-9 and MMP-14 gene expression by 92% and 50%, respectively, and impaired EGF-stimulated tumor cell invasion. These results suggest that PEA3 is regulated by EGFR and that the elevated PEA3 expression detected in human ovarian cancer may divert cells to a more invasive phenotype by regulating MMP-9 and MMP-14.

UR - http://www.scopus.com/inward/record.url?scp=34250180482&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34250180482&partnerID=8YFLogxK

U2 - 10.1158/1541-7786.MCR-07-0019

DO - 10.1158/1541-7786.MCR-07-0019

M3 - Article

C2 - 17475671

AN - SCOPUS:34250180482

VL - 5

SP - 413

EP - 421

JO - Molecular Cancer Research

JF - Molecular Cancer Research

SN - 1541-7786

IS - 5

ER -