Abnormal Sialylation Promotes Chemotherapy Resistance in Bladder Cancer via the PI3K-AKT-mTOR Signaling Pathway

Background: Aberrant glycosylation is closely associated with tumor progression, changes in the tumor microenvironment, and chemoresistance. This study aimed to identify prognostic sialylation-related genes in bladder cancer and define the role of ST3GAL6 in gemcitabine–cisplatin resistance. Methods: Molecular subtype analysis, prognostic analysis, and risk model construction were performed for sialylation-related genes using transcriptomic data and clinical information from the TCGA database. GC-resistant bladder cancer cell models were established for transcriptomic sequencing and untargeted metabolomic analysis. Cell proliferation and drug sensitivity assays were performed to evaluate the function of ST3GAL6. The regulatory relationship between IGF2BP3, ST3GAL6, and the PI3K pathway was further assessed by combining database analysis with molecular experiments. Results: Sialylation-related molecular patterns were associated with patient prognosis and tumor microenvironment features, particularly fibroblast-related characteristics, in bladder cancer. The key model gene ST3GAL6 was upregulated in bladder cancer tissues and was closely associated with prognosis. In GC-resistant bladder cancer cells, ST3GAL6 expression was significantly increased and accompanied by enhanced sialylation activity. ST3GAL6 promoted bladder cancer cell proliferation and reduced sensitivity to cisplatin and gemcitabine, at least in part through the PI3K-AKT-mTOR pathway. IGF2BP3 was also upregulated in resistant cells, is positively correlated with ST3GAL6, and may help maintain ST3GAL6’s expression by stabilizing its mRNA. Conclusions: Our findings suggest that aberrant sialylation is involved in bladder cancer progression and GC resistance. The IGF2BP3-ST3GAL6-PI3K/AKT/mTOR signaling axis may contribute to this process and may serve as a potential biomarker and therapeutic target in bladder cancer.