Microenvironmental regulation of membrane type 1 matrix metalloproteinase activity in ovarian carcinoma cells via collagen-induced EGR1 expression

J Biol Chem. 2007 Feb 16;282(7):4924-31. doi: 10.1074/jbc.M608428200. Epub 2006 Dec 11.

Abstract

Late stage ovarian cancer is characterized by disseminated intraperitoneal metastasis as secondary lesions anchor in the type I and III collagen-rich submesothelial matrix. Ovarian carcinoma cells preferentially adhere to interstitial collagen, and collagen-induced integrin clustering up-regulates the expression of the transmembrane collagenase membrane type 1 matrix metalloproteinase (MT1-MMP). Collagenolytic activity is important in intraperitoneal metastasis, potentiating invasion through the mesothelial cell layer and colonization of the submesothelial collagen-rich matrix. The objective of this study was to elucidate a potential mechanistic link between collagen adhesion and MT1-MMP expression. Our results indicate that culturing cells on three-dimensional collagen gels, but not thin layer collagen or synthetic three-dimensional hydrogels, results in rapid induction of the transcription factor EGR1. Integrin signaling through a SRC kinase-dependent pathway is necessary for EGR1 induction. Silencing of EGR1 expression using small interfering RNA abrogated collagen-induced MT1-MMP expression and inhibited cellular invasion of three-dimensional collagen gels. These data support a model for intraperitoneal metastasis wherein collagen adhesion and clustering of collagen binding integrins activates integrin-mediated signaling via SRC kinases to induce expression of EGR1, resulting in transcriptional activation of the MT1-MMP promoter and subsequent MT1-MMP-catalyzed collagen invasion. This model highlights the role of unique interactions between ovarian carcinoma cells and interstitial collagens in the ovarian tumor microenvironment in inducing gene expression changes that potentiate intraperitoneal metastatic progression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion / genetics
  • Collagen Type I / metabolism*
  • Collagen Type II / metabolism*
  • Early Growth Response Protein 1 / genetics
  • Early Growth Response Protein 1 / metabolism*
  • Extracellular Matrix / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic* / drug effects
  • Gene Expression Regulation, Neoplastic* / genetics
  • Humans
  • Integrins / genetics
  • Integrins / metabolism
  • Matrix Metalloproteinase 14 / biosynthesis*
  • Matrix Metalloproteinase 14 / genetics
  • Neoplasm Metastasis
  • Neoplasm Proteins / biosynthesis*
  • Neoplasm Proteins / genetics
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology
  • Peritoneal Neoplasms / genetics
  • Peritoneal Neoplasms / metabolism
  • Peritoneal Neoplasms / pathology
  • Peritoneal Neoplasms / secondary
  • Promoter Regions, Genetic
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / pharmacology
  • Signal Transduction
  • Transcription, Genetic
  • Tumor Cells, Cultured
  • src-Family Kinases / genetics
  • src-Family Kinases / metabolism

Substances

  • Collagen Type I
  • Collagen Type II
  • EGR1 protein, human
  • Early Growth Response Protein 1
  • Integrins
  • Neoplasm Proteins
  • RNA, Small Interfering
  • src-Family Kinases
  • Matrix Metalloproteinase 14