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Angiogenesis, Metastasis, and the Cellular Microenvironment

Interplay between Epidermal Growth Factor Receptor and Janus Kinase 3 Regulates Polychlorinated Biphenyl–Induced Matrix Metalloproteinase-3 Expression and Transendothelial Migration of Tumor Cells

¹ Molecular Neuroscience and Vascular Biology Laboratory, Department of Surgery and ² College of Agriculture, University of Kentucky, Lexington, Kentucky

Requests for reprints: Michal Toborek, Molecular Neuroscience and Vascular Biology Laboratory, Department of Surgery, Division of Neurosurgery, University of Kentucky Medical Center, 593 Wethington Building, 900 South Limestone, Lexington, KY 40536. Phone: 859-323-4094; Fax: 859-323-2705. E-mail: mjtobo00{at}uky.edu

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. (Mol Cancer Res 2006;4(6):361–70)

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