Interplay between epidermal growth factor receptor and janus kinase 3 regulates polychlorinated biphenyl-induced matrix metalloproteinase-3 expression and transendothelial migration of tumor cells

Sung Yong Eum, Yong Woo Lee, Bernhard Hennig, Michal Toborek

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

We hypothesize that environmental toxicants, such as polychlorinated biphenyl congeners, can activate vascular endothelial cells and thus increase formation of blood-borne metastases. This study indicates that exposure of human microvascular endothelial cells to 2,2′,4,6,6′-pentachlorobiphenyl can stimulate transendothelial migration of tumor cells through up-regulation of matrix metalloproteinase (MMP)-3. In a series of experiments with specific small interfering RNA and pharmacologic inhibitors, we provide evidence that 2,2′,4,6,6′-pentachlorobiphenyl can activate epidermal growth factor receptor (EGFR) and Janus kinase 3 (JAK3) in a closely coordinated and cross-dependent fashion. Activated EGFR and JAK3 stimulate in concert c-Jun NH2-terminal kinase and extracellular signal-regulated kinase 1/2 as well as increase DNA-binding activity of transcription factors activator protein-1 and polyomavirus enhancer activator protein 3, leading to transcriptional up-regulation of MMP-3 expression. These results indicate that the interplay among EGFR, JAK3, and mitogen-activated protein kinases, such as c-Jun NH2-terminal kinase and extracellular signal-regulated kinase 1/2, is critical for polychlorinated biphenyl-induced MMP-3 expression and accelerated transendothelial migration of tumor cells.

Original languageEnglish (US)
Pages (from-to)361-370
Number of pages10
JournalMolecular Cancer Research
Volume4
Issue number6
DOIs
StatePublished - Jun 1 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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