EGR1 Enhances Lymphangiogenesis via SOX18-Mediated Activation of JAK2/STAT3 Pathway

BACKGROUND: Lymphangiogenesis is a process involved in the pathogenesis of many diseases. Identifying key molecules and pathway targeting this process is critical for lymphatic regeneration-associated disorders. EGR1 is a transcription factor, but its function in lymphangiogenesis is not yet known. This study is aimed at exploring the functional activity and molecular mechanism of EGR1 implicated in lymphangiogenesis. METHODS: The CCK-8 method, transwell migration assay, and tube formation assay were used to detect the cell viability, motility, and tube formation of HDLEC cells, respectively. The luciferase reporter assay was applied to detect the impact of EGR1 on SOX18 promoter activity. CHIP assay was used to analyze the direct binding of EGR1 to the SOX18 promoter. qRT-PCR and Western blot analysis were performed to investigate molecules and pathway involved in lymphangiogenesis. RESULTS: The EGR1 ectopic expression markedly increased the cell growth, mobility, tube formation, and the expression of lymphangiogenesis-associated markers (LYVE-1 and PROX1) in HDLEC cells. EGR1 interacted with the SXO18 gene promoter and transcriptionally regulated the SXO18 expression in HDLEC cells. Silencing of SOX18 abrogated the promotional activities of EGR1 on the cell viability, mobility, tube formation, and LYVE-1/PROX1 expression in HDLEC cells. SOX18 overexpression activated JAK/STAT signaling, which resulted in an increase in lymphangiogenesis in HDLEC cells. CONCLUSIONS: ERG1 can promote lymphangiogenesis, which is mediated by activating the SOX18/JAK/STAT3 cascade. ERG1 may serve as a promising target for the therapy of lymphatic vessel-related disorders.