Inhibiting Interleukin-6/Signal Transducers and Activators of Transduction-3/Hypoxia-Inducible Factor-1α Signaling Pathway Suppressed the Growth of Infantile Hemangioma

Abstract

Objective This study aims to evaluate the expression of interleukin 6 (IL-6) in patients with infantile hemangioma (IH) and investigate the role of the IL-6/signal transducers and activators of transduction-3 (STAT3)/hypoxia-inducible factor-1α (HIF-1α) pathways in the progression of IH. Methods Serum samples were obtained from the patients with IH and normal infants to measure IL-6 expression. Hemangioma-derived stem cells (HemSCs) were transfected with small interfering RNA (siRNA) targeting IL-6, HIF-1α, or STAT3. Then, cell viability and wound healing assays were conducted. After that, the HemSC tumor mouse model was established. The in vivo anticancer effect of the IL-6 inhibitor was investigated. Results The patients with IH had much higher IL-6 levels compared with the healthy controls (p = 0.005). HemSCs transfected with IL-6 siRNA had significantly lower viability and migration rates than normal HemSCs. HemSCs transfected with STAT3 siRNA or HIF-1α siRNA had similar tendencies. On tumor-bearing mice, the IL-6 inhibitor treatment significantly delayed tumor growth. Compared with the control group, caspase-3 was significantly increased in the IL-6 inhibitor group (p < 0.05), whereas Ki-67 was decreased in the IL-6 inhibitor group (p < 0.05). In the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, the IL-6 inhibitor group had much higher apoptosis rates than the controls (p < 0.05). Conclusion Our findings indicate that inhibiting the IL-6/STAT3/HIF-1α signaling pathways could suppress IH growth.

Mechanism of the HIF‐1α/VEGF/VEGFR‐2 pathway in the proliferation and apoptosis of human haemangioma endothelial cells

“…27 Silencing of HIF-1a limits the viability and migration rate of HemECs. 28 Propranolol blocks the proliferation, tube formation, and migration of HA cells via the HIF-1α dependent mechanisms. 29 Thus HIF-1α amplified the more aggressive behaviour of HemECs.…”

“…Likewise, repression of the HIF‐1a‐VEGF axis leads to the antiproliferative property of curcumin in HemECs 27 . Silencing of HIF‐1a limits the viability and migration rate of HemECs 28 . Propranolol blocks the proliferation, tube formation, and migration of HA cells via the HIF‐1α dependent mechanisms 29 .…”

Transcriptional data analysis reveals the association between infantile hemangiomas and venous malformations

“…Many vascular malformations share similar aberrant molecular signaling pathways with cancers and inflammatory disorders ( Pang et al, 2020 ). It is reported that inhibiting the IL-6/STAT3/HIF-1α signaling pathways could suppress IH growth ( Maimaiti et al, 2022 ). These results indicated that the hub genes were involved in several signaling pathways mediated by growth factor and immune gene, which play a critical role in regulating endothelial cells.…”

Emerging role of hypoxia-inducible factor-1α in inflammatory autoimmune diseases: A comprehensive review

“…IL-6 binds to gp160, then activates STAT3/HIF-1α, which promotes the proliferation of Foxp3 + regulatory T (Treg) cells and reduces activity and migration of hemangioma-derived stem cells ( 25 , 26 ). IL-17 induces defective autophagy through interacting with STAT3/HIF-1α and causes inflammatory death of keloid fibroblasts ( 27 ).…”