Targeting ESM1 via SOX4 Promotes the Progression of Infantile Hemangioma through the PI3K/AKT Signaling Pathway

Pediatrics Life Sciences Medicine Oncology Immunology
infantile hemangioma CD31+ HEMECs SOX4 proliferation angiogenesis

Infantile Hemangioma (IH) is the most common benign vascular tumor in children, with an incidence rate of approximately 4%-10%. Although most IH cases resolve spontaneously, some cases may lead to permanent pigmentation, fibrous tissue accumulation, and scarring, affecting the appearance and quality of life of children. Additionally, certain IH cases may be accompanied by bleeding, pain, infection, and ulcers, and can even result in severe complications such as organ failure, visual impairment, restricted joint movement, and breathing difficulties. Therefore, in-depth research into the pathogenesis of IH and the identification of new therapeutic targets are of significant clinical importance.

SOX4, a member of the SOX gene family, is a key transcription factor that plays an important role in tumor angiogenesis. Studies have shown that SOX4 is highly expressed in various malignant tumors and promotes tumor progression by regulating signaling pathways such as PI3K/AKT. However, the mechanism of SOX4 in IH has not been fully elucidated. Therefore, this study aims to explore the function of SOX4 in IH development and its underlying mechanisms, providing new targets for IH treatment.

Source of the Paper

This paper was co-authored by Yanan Li, Meng Kong, Tong Qiu, and Yi Ji, with the research team from the Division of Oncology, Department of Pediatric Surgery at West China Hospital, Sichuan University, and the Department of Pediatric Surgery at the Children’s Hospital affiliated with Shandong University. The paper was published on October 9, 2024, in the journal Precision Clinical Medicine, with the DOI: 10.1093/pcmedi/pbae026.

Research Process and Results

1. Expression and Function of SOX4 in IH Tissues

The research team first screened transcription factors in IH microtumors through RNA sequencing (RNA-seq) and found that SOX4 is closely associated with IH, which was further validated in IH tissues. The results showed that SOX4 is highly expressed in IH tissues, particularly in the proliferative phase, with significantly higher mRNA and protein levels compared to the involuting phase. Immunohistochemistry (IHC) and immunofluorescence (IF) experiments further confirmed that SOX4 is primarily localized in the nucleus, with stronger expression in proliferative-phase IH tissues.

Next, the team investigated the effects of SOX4 on the biological behavior of CD31+ hemangioma-derived endothelial cells (HemECs) through in vitro cell experiments. The experiments demonstrated that SOX4 promotes the proliferation, migration, and angiogenesis of HemECs. Additionally, RNA-seq analysis revealed that Endothelial Cell-Specific Molecule 1 (ESM1) is a downstream target gene in HemECs with low SOX4 expression. Through 3D microtumor and animal experiments, the team further confirmed the independent roles of SOX4 and ESM1 in promoting tumor progression.

2. SOX4 Regulates ESM1 Expression via the PI3K/AKT Signaling Pathway

The research team predicted the binding of SOX4 to the ESM1 promoter region through database analysis and confirmed it using chromatin immunoprecipitation sequencing (ChIP-seq). The experiments showed that SOX4 activates the PI3K/AKT signaling pathway by binding to the ESM1 promoter, thereby promoting the migration and angiogenic behaviors of HemECs. Moreover, the activated PI3K/AKT signaling pathway upregulated the expression of GLUT-1, a biomarker of IH, enhancing cell proliferation and ultimately driving IH progression.

3. Role of ESM1 in IH Progression

The team further investigated the role of ESM1 in IH progression. The results showed that ESM1 expression is significantly higher in proliferative-phase IH tissues than in involuting-phase tissues and positively correlates with SOX4 expression. By transfecting ESM1 siRNA and overexpression plasmids, the team found that low ESM1 expression significantly inhibited the proliferation, migration, and angiogenesis of HemECs, while ESM1 overexpression promoted these biological behaviors. Additionally, ESM1 promoted IH progression by activating the PI3K/AKT signaling pathway.

4. Role of the SOX4-ESM1 Signaling Axis in IH Progression

To further validate the role of the SOX4-ESM1 signaling axis in IH progression, the team conducted subcutaneous tumor formation experiments in nude mice. The results showed that low SOX4 expression significantly inhibited tumor growth, while ESM1 overexpression promoted tumor growth. Simultaneously, low SOX4 expression combined with ESM1 overexpression partially restored tumor growth. Immunohistochemical analysis revealed that the microvessel density (MVD) in tumor tissues was significantly reduced in the low SOX4 group but significantly increased in the ESM1 overexpression group. These results indicate that SOX4 promotes IH progression by regulating ESM1 expression.

Conclusion and Significance

This study found that 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. The study revealed the molecular mechanism by which SOX4 activates the PI3K/AKT signaling pathway to regulate ESM1 expression, thereby promoting angiogenesis and tumor progression in IH. This discovery provides new insights and targets for IH treatment, with significant scientific and clinical value.

Research Highlights

  1. High Expression of SOX4 in IH: The study first confirmed the high expression of SOX4 in IH tissues, particularly in the proliferative phase, suggesting its important role in IH progression.
  2. Discovery of the SOX4-ESM1 Signaling Axis: The study revealed the molecular mechanism by which SOX4 regulates ESM1 expression to activate the PI3K/AKT signaling pathway, promoting IH progression.
  3. Proposal of New Therapeutic Targets: The SOX4/ESM1 axis as a potential therapeutic target for IH provides a new direction for IH treatment.

Other Valuable Information

The study also found a positive feedback loop between ESM1 and Vascular Endothelial Growth Factor A (VEGF-A). VEGF-A stimulates ESM1 expression through phosphorylation and activation of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), while ESM1 replaces fibronectin-bound VEGF-A, increasing the bioavailability of VEGF-A and its mediated signaling. This discovery provides a new strategy for inhibiting angiogenesis, and future studies may control IH progression by targeting ESM1.

Future Research Directions

Although this study has made significant progress, there are still some limitations. For example, the clinical data and samples were from a single center, and the sample size was relatively small. Future research will expand the sample size and explore the effects of drugs (e.g., inhibitors) targeting the SOX4-ESM1 signaling axis on IH progression. Additionally, the integration of new technologies such as gene editing and bioprinting may provide new ideas and tools for targeted therapy of the SOX4-ESM1 axis.