Interleukin-6 (IL-6) triggers the malignancy of hemangioma cells via activation of HIF-1α/VEGFA signals.

Hemangioma (HA) is tumor formed by hyper-proliferation of vascular endothelial cells. The roles of interleukins on the progression of HA are not well illustrated. Our present study revealed that the expression of interleukin -6 (IL-6) and IL-8 in HA cells were significantly increased as compared with that in the human umbilical vein endothelial cell (HUVEC) cells. Targeted inhibition of IL-6, while not IL-8, can significantly suppress the proliferation and migration of HA cells. IL-6 treatment can increase the expression of vascular endothelial growth factor A (VEGFA), while had no significant effect on the expression of basic fibroblast growth factor (bFGF), in HA cells. Deletion of VEGFA can abolish IL-6 induced progression of HA, suggesting the essential role of VEGFA in IL-6 induced HA development. The specific inhibitor of hypoxia-inducible factor (HIF)-1α, while not Sp1, NF-κB, or AP1, abolished IL-6 induced VEGFA expression. Over expression of HIF-1α can attenuate anti-IL-6 suppressed expression of VEGFA in HA cells. Furthermore, IL-6 triggered the expression, nuclear translocation, and transcription activities of HIF-1α in HA cells via increasing its binding with the signal transducer and activator of transcription-3 (STAT3). STAT3 inhibitor CPA7 or si-STAT3 can abolish IL-6 induced upregulation of HIF-1α in HDEC cells. Collectively, our study revealed that IL-6 can trigger the malignancy of HA cells via induction of proliferation and migration. The activation of STAT3/HIF-1α/VEGFA signal was essential for this process. It suggested that IL-6/STAT3/HIF-1α/VEGFA signal may represent a novel therapeutic target for human HA treatment.