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.

Keywords

infantile hemangioma - signal transducers and activators of transduction-3 - hypoxia inducible factor-1α - apoptosis - interleukin 6

Ethical Approval

This study was conducted in accordance with the Declaration of Helsinki and approved by the ethics committee of Children's Hospital of Xinjiang Uygur Autonomous Region. The Animal Care and Use Committee of Children's Hospital of Xinjiang Uygur Autonomous Region granted a project license to perform the animal experiments (grant no.: 2020101967).

Data and Materials

All data generated or analyzed during this study are included in this published article.

Authors' Contributions

A.M. and Y.A. conceived of the study, J.H. and L.Z. participated in its design, and S.-X.L. coordination and helped to draft the manuscript. All authors read and approved the final manuscript.

 ∗ These authors have contributed equally to this study and retain the first authorship.

Publikationsverlauf

Eingereicht: 11. November 2021

Angenommen: 17. März 2022

Artikel online veröffentlicht:
12. Juli 2022

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