Interplay between epidermal growth factor receptor and Janus kinase 3 regulates polychlorinated biphenyl-induced matrix metalloproteinase-3 expression and transendothelial migration of tumor cells.
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 NH(2)-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 NH(2)-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.
Eum
Sung Yong
SY
Molecular Neuroscience and Vascular Biology Laboratory, Department of Surgery, University of Kentucky, Lexington, USA.
Lee
Yong Woo
YW
Hennig
Bernhard
B
Toborek
Michal
M
D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002199:Capillary Permeability; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D004268:DNA-Binding Proteins / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D004730:Endothelium, Vascular / Q000187:drug effects*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D053616:Janus Kinase 3; D019278:Matrix Metalloproteinase 3 / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases; D009362:Neoplasm Metastasis; D011078:Polychlorinated Biphenyls / Q000378:metabolism / Q000633:toxicity*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C060759:enhancer-binding protein AP-3; D011078:Polychlorinated Biphenyls; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019278:Matrix Metalloproteinase 3; C417207:2,2',4,6,6'-pentachlorobiphenyl