Interleukin-6 induces vascular endothelial growth factor-C expression via Src-FAK-STAT3 signaling in lymphatic endothelial cells

Yu Han Huang, Hung Yu Yang, Shiu Wen Huang, George Ou, Ya Fen Hsu, Ming Jen Hsu

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Article numbere0158839
JournalPLoS One
Volume11
Issue number7
DOIs
Publication statusPublished - Jul 1 2016

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non-specific protein-tyrosine kinase
vascular endothelial growth factor C
Vascular Endothelial Growth Factor C
Focal Adhesion Protein-Tyrosine Kinases
Endothelial cells
interleukin-6
endothelial cells
Interleukin-6
Endothelial Cells
Lymphangiogenesis
Tumors
luciferase
Luciferases
neoplasms
Neoplasms
Focal Adhesion Kinase 2
promoter regions
Phosphorylation
small interfering RNA
cell movement

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Interleukin-6 induces vascular endothelial growth factor-C expression via Src-FAK-STAT3 signaling in lymphatic endothelial cells. / Huang, Yu Han; Yang, Hung Yu; Huang, Shiu Wen; Ou, George; Hsu, Ya Fen; Hsu, Ming Jen.

In: PLoS One, Vol. 11, No. 7, e0158839, 01.07.2016.

Research output: Contribution to journalArticle

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