title: Interleukin-6 Induces Vascular Endothelial Growth Factor-C Expression via Src-FAK-STAT3 Signaling in Lymphatic Endothelial Cells.
abstract: Elevated serum interleukin-6 (IL-6) levels correlates with tumor grade and poor prognosis in cancer patients. IL-6 has been shown to promote tumor lymphangiogenesis through vascular endothelial growth factor-C (VEGF-C) induction in tumor cells. We recently showed that IL-6 also induced VEGF-C expression in lymphatic endothelial cells (LECs). However, the signaling mechanisms involved in IL-6-induces VEGF-C induction in LECs remain incompletely understood. In this study, we explored the causal role of focal adhesion kinase (FAK) in inducing VEGF-C expression in IL-6-stimulated murine LECs (SV-LECs). FAK signaling blockade by NSC 667249 (a FAK inhibitor) attenuated IL-6-induced VEGF-C expression and VEGF-C promoter-luciferase activities. IL-6's enhancing effects of increasing FAK, ERK1/2, p38MAPK, C/EBPβ, p65 and STAT3 phosphorylation as well as C/EBPβ-, κB- and STAT3-luciferase activities were reduced in the presence of NSC 667249. STAT3 knockdown by STAT3 siRNA abrogated IL-6's actions in elevating VEGF-C mRNA and protein levels. Moreover, Src-FAK signaling blockade reduced IL-6's enhancing effects of increasing STAT3 binding to the VEGF-C promoter region, cell migration and endothelial tube formation of SV-LECs. Together these results suggest that IL-6 increases VEGF-C induction and lymphangiogenesis may involve, at least in part, Src-FAK-STAT3 cascade in LECs.
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Han
authors.initials: YH
authors.lastname: Huang
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan.|Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Hung-Yu
authors.initials: HY
authors.lastname: Yang
authors.affiliation: Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Shiu-Wen
authors.initials: SW
authors.lastname: Huang
authors.affiliation: Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: George
authors.initials: G
authors.lastname: Ou
authors.affiliation: Division of General Surgery, Department of Surgery, Landseed Hospital, Taoyuan, Taiwan.
authors.forename: Ya-Fen
authors.initials: YF
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ming-Jen
authors.initials: MJ
authors.lastname: Hsu
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D015151:Immunoblotting; D015850:Interleukin-6 / Q000494:pharmacology*; D042583:Lymphangiogenesis / Q000187:drug effects; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D042582:Vascular Endothelial Growth Factor C; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases