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 tumour in children, yet its pathogenesis remains incompletely understood. Research has established a strong association between SOX4 and tumour blood vessel formation. However, the specific role of SOX4 in IH progression has not been clearly defined. 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 and facilitating drug development. Methods The transcription factor SOX4, which is associated with IH, was identified through RNA-seq screening of IH microtumours and validated in IH tissue samples. Cell experiments were conducted to investigate the impact of SOX4 on the biological behavior of CD31+ HemECs and the PI3K/AKT pathway. Furthermore, RNA-seq analysis was performed on CD31+ HemECs exhibiting low levels of SOX4, leading to the identification of the downstream gene ESM1, which is regulated by SOX4. The targeting relationship between SOX4 and ESM1 was confirmed through database predictions and ChIP-PCR assays. Finally, the influence of the SOX4-ESM1 signaling axis on tumour growth was further elucidated through 3D microtumour models and tumour formation experiments in nude mice. Results During the proliferating phase, SOX4 was highly expressed in IH tissue samples and was shown to enhance the proliferation, migration, and angiogenesis of CD31+ HemECs in vitro. SOX4 was observed to bind to the promoter of ESM1, thereby transcriptionally upregulating the ESM1-mediated PI3K/AKT signaling pathway and ultimately promoting the progression of IH. The pro-proliferative effect of SOX4 on CD31+ HemECs was dependent on the expression of ESM1. Through IH 3D microtumour and in vitro animal experiments, it was demonstrated that both SOX4 and ESM1 are tumourigenic genes that independently promote tumour progression and that tumour growth could be partially reversed by knocking down SOX4 and overexpressing ESM1. 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.