Abstract
OBJECTIVE: To investigate the role of ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (ST3Gal1) in endometrial cancer (EC) progression and its potential as a therapeutic target to enhance the efficacy of antiangiogenic treatment. METHODS: ST3Gal1 expression and its clinical relevance were analyzed in EC tissues. Functional assays evaluated its effects on vascular endothelial growth factor-A (VEGF-A) expression, epithelial-mesenchymal transition (EMT), and cell invasiveness. Mechanistic studies, including Duolink proximity ligation assays and co-immunoprecipitation, examined ST3Gal1-VEGF-A interactions. ST3Gal1 was inhibited genetically or pharmacologically using soyasaponin I (SsaI), both in vitro and in xenograft models, alone or combined with bevacizumab. Angiogenic and EMT marker expression and focal adhesion kinase (FAK)/paxillin pathway activation were assessed. RESULTS: ST3Gal1 was amplified and overexpressed in EC and correlated with advanced stage, deep myometrial invasion, and poor prognosis. It directly glycosylated VEGF-A and activated FAK/paxillin signaling, promoting VEGF-A expression and EMT. ST3Gal1 inhibition via SsaI reduced VEGF-A signaling, reversed EMT marker expression, and suppressed cell migration and invasion, particularly in RL95-2 cells. In vivo, SsaI significantly inhibited tumor growth and angiogenesis, with the most pronounced effect observed in combination with bevacizumab. Dual treatment disrupted ST3Gal1-VEGF-A interactions and downregulated angiogenic and EMT markers. CONCLUSION: ST3Gal1 promotes EC progression by enhancing VEGF-A signaling and EMT via the FAK/paxillin pathway. Its inhibition improves the efficacy of antiangiogenic therapy, supporting ST3Gal1 as a promising therapeutic target to overcome anti-VEGF-A resistance in advanced EC.