Targeting ESM1 via SOX4 promotes the progression of infantile hemangioma through the PI3K/AKT signaling pathway

Abstract

Background: Infantile hemangioma (IH) is the most prevalent benign vascular tumor in children, yet its pathogenesis remains incompletely understood. Research has established a strong association between SOX4 and tumor blood vessel formation. The objective of this study was to investigate the function and underlying mechanism of SOX4 in IH development with the aim of identifying novel therapeutic targets.

Methods: We identified the transcription factor SOX4 associated with IH through RNA-seq screening of IH microtumors and validated it in IH tissues. The effect of SOX4 on the biological behavior of CD31+ hemangioma-derived endothelial cells (HemECs) was investigated via in vitro cell experiments. In addition, RNA-seq analysis was performed on CD31+ HemECs with low expression levels of SOX4, and the target genes of SOX4 were identified. Finally, the effect of SOX4 on tumor angiogenesis was further elucidated through 3D microtumor and animal experiments.

Results: SOX4 is highly expressed in IH tissues and promotes the proliferation, migration, and angiogenesis of CD31+ HemECs. In addition, SOX4 binds to the endothelial cell-specific molecule 1 (ESM1) promoter to promote the progression of the PI3K/AKT signaling pathway. Finally, through IH 3D microtumor and animal experiments, SOX4 and ESM1 are shown to be tumorigenic genes that independently promote tumor progression.

Conclusions: SOX4 plays a crucial role in the progression of IH, and the SOX4/ESM1 axis may serve as a novel biomarker and potential therapeutic target for IH.

Keywords

infantile hemangioma / CD31+ HemECs / SOX4 / proliferation / angiogenesis

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grants No. 82473553 and 82273556), the Key Project in the Science & Technology Program of Sichuan Province (Grants No. 2022YFS0233 and 2022YFS0225), the Postdoctoral Foundation of West China Hospital of Sichuan University (Grant No. 2023HXBH056), the Project of Natural Science Foundation of Shandong Province (Grant No. ZR2022MH229), the ‘0 to 1’ Project of Sichuan University (Grant No. 2022SCUH0033), the Med-X Center for Informatics Funding Project (Grant No. YGJC004), the 1·3·5 Project for Disciplines of Excellence-Clinical Research Incubation Project of West China Hospital of Sichuan University (Grants No. 2023HXFH004, 2020HXFH048 and 2019HXFH056), and the 1·3·5 Project for Disciplines of Excellence-Clinical Research Interdisciplinary Innovation Project of West China Hospital of Sichuan University (Grant No. ZYJC21060). We thank Li Li and Chunjuan Bao (Institute of Clinical Pathology, West China Hospital, Sichuan University) for performing the histological staining.

Author contributions

Yanan Li (Data curation, Formal analysis, Investigation, Methodology, Software), Meng Kong (Conceptualization, Data curation, Methodology, Writing—original draft), Tong Qiu (Data curation), and Yi Ji (Funding acquisition, Methodology, Supervision, Writing—review & editing).

Supplementary data

Supplementary data is available at PCMEDI Journal online.

Conflict of interest

None declared.

Ethics approval and consent to participate

The study was approved by the West China Hospital of Sichuan University Biomedical Research Ethics Committee (No. 2017-414), and informed consent was obtained from all participants or legal guardians.

Data Availability

All relevant data are contained within the article. The original contributions presented in the study are included in the supplementary material. Additional data supporting the findings of this article are available from the corresponding author upon reasonable request.

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