Unlocking the role of prostate transmembrane androgen inducible protein 1 in gemcitabine resistance: modulation of P38-mitogen-activated protein kinase/C–C motif chemokine ligand 2 and M2 macrophage polarization in bladder cancer

Bladder cancer (BLCA) is a highly aggressive malignancy, with chemotherapy resistance being a significant factor in treatment failure. In the tumor microenvironment, M2 macrophage polarization is essential for immune suppression and treatment resistance. Key genes linked to M2 macrophage polarization and gemcitabine resistance in BLCA are examined in this work, along with possible underlying processes. Bioinformatics analyses were performed to identify differentially expressed genes in BLCA. Key hub genes related to M2 macrophage polarization and gemcitabine resistance were identified using various bioinformatics tools, including Cibersort, weighted gene coexpression network analysis, and gene set enrichment analysis. The effects of prostate transmembrane androgen inducible protein 1 (PMEPA1) silencing on cell viability, gemcitabine resistance, and macrophage polarization were further assessed using reverse transcription-quantitative PCR, Western blot, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, ELISA, and flow cytometry. Bioinformatics analysis revealed that PMEPA1 is a core gene associated with M2 macrophage polarization and gemcitabine resistance. Knockdown of PMEPA1 in BLCA cell lines reduced cell viability and enhanced gemcitabine sensitivity. Silencing of PMEPA1 also promoted M1 macrophage polarization while decreasing M2 macrophage polarization, as shown by the downregulation of cluster of differentiation (CD) 163 + and upregulation of CD86 + . Mechanistically, PMEPA1 regulated the P38-mitogen-activated protein kinase (MAPK)/C-C motif chemokine ligand 2 (CCL2) axis, leading to M2 macrophage polarization. Our findings suggest that PMEPA1 plays a crucial role in regulating M2 macrophage polarization and gemcitabine resistance in BLCA by activating the P38-MAPK/CCL2 signaling pathway.