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.
Highlights
Metastatic spread of tumor cells remains the major cause of death in cancer patients [1, 2]
Antibodies against Src phosphorylated at Tyr416, focal adhesion kinase (FAK), FAK phosphorylated at Tyr397, p38MAPK, p38MAPK phosphorylated at Thr180/Tyr182, ERK1/2, ERK1/2 phosphorylated at Thr202/Tyr204, C/EBPβ phosphorylated at Thr235, and signal transducer and activator of transcription 3 (STAT3) phosphorylated at Tyr705 were purchased from Cell Signaling (Danvers, MA, USA)
Confirming the inhibitory effects of NSC 667249, a marked reduction in IL-6/soluble form of IL-6 receptor (IL-6R) (sIL-6R)-induced FAK phosphorylation was observed in SV-lymphatic endothelial cells (LECs) exposed to NSC 667249 (Fig 1D). These results suggest that IL-6/sIL-6R-induced vascular endothelial growth factor-C (VEGF-C) expression is attributed to FAK signaling in SV-LECs
Summary
Metastatic spread of tumor cells remains the major cause of death in cancer patients [1, 2]. Tumor cells access to the systemic circulation and invade surrounding tissues by releasing growth factors or cytokines to stimulate angiogenesis and lymphangiogenesis [3]. Angiogenesis and lymphangiogenesis, the major routes for tumor metastasis, represent rational targets for therapeutic intervention. Lymphangiogenesis, in contrast to angiogenesis, has been less thoroughly explored. There have been growing evidence that lymphangiogenesis is increased in various malignancies. Patients with tumor lymphangiogenesis have less favorable outcome [5]. Suppression of tumor lymphangiogenesis markedly reduced tumor metastasis in xenograft murine models [6]. Understanding the molecular signaling cascades that modulate lymphangiogenesis is mandatory for developing novel therapeutic strategies for cancer treatment
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