IGF2BP3 enhances paclitaxel resistance in bladder urothelial carcinoma by recognizing m6A-modified CENPA mRNA.

Bladder urothelial carcinoma (BUC) is associated with poor prognosis and chemoresistance. The RNA-binding protein IGF2BP3 has been implicated in the progression and drug resistance of various cancers, but its role in UC remains underexplored. This study aimed to investigate the role of IGF2BP3 in regulating CENPA mRNA stability and its contribution to UC malignancy and paclitaxel (PTX) resistance. We analyzed human BUC cell lines (UMUC3, T24) and their paclitaxel-resistant counterpart (T24/R). The interaction between IGF2BP3 and CENPA mRNA was assessed using RNA immunoprecipitation (RIP), MeRIP-qPCR, and dual-luciferase reporter assays. RNA stability was measured with actinomycin D treatment. Cell migration, invasion, and clonogenic assays were performed to evaluate the impact of IGF2BP3 and CENPA modulation on tumor behavior. In vivo tumorigenicity and paclitaxel response were evaluated using xenograft mouse models. IGF2BP3 directly binds to m6A-modified CENPA mRNA and enhances its stability, thereby sustaining its expression in BUC. IGF2BP3 knockdown markedly decreased CENPA mRNA and protein levels and increased paclitaxel sensitivity. CENPA overexpression restored the migratory, invasive, and clonogenic capacities of IGF2BP3-silenced cells under paclitaxel treatment, whereas mutation of the m6A site abolished this rescue effect, indicating m6A dependency. In vivo, IGF2BP3 silencing suppressed tumor growth and enhanced paclitaxel sensitivity in T24/R-derived xenografts, which was partially reversed by CENPA overexpression. IGF2BP3 promotes malignant phenotype and paclitaxel resistance in BUC by stabilizing CENPA mRNA. Targeting the IGF2BP3-CENPA axis may provide a novel therapeutic strategy to overcome chemoresistance in BUC.