title: Interplay between epidermal growth factor receptor and Janus kinase 3 regulates polychlorinated biphenyl-induced matrix metalloproteinase-3 expression and transendothelial migration of tumor cells.
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 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.
authors.affiliation: Molecular Neuroscience and Vascular Biology Laboratory, Department of Surgery, University of Kentucky, Lexington, USA.
authors.forename: Sung Yong
authors.initials: SY
authors.lastname: Eum
authors.forename: Yong Woo
authors.initials: YW
authors.lastname: Lee
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hennig
authors.forename: Michal
authors.initials: M
authors.lastname: Toborek
mesh_terms: 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
chemical_list: 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