Identification of MYC co-expression gene: POLR3G is associated with cell senescence, immunotherapy, chemotherapy responses, and clinical prognosis in bladder cancer patients

• POLR3G is a key MYC-co-expressed gene and independent prognostic biomarker in BLCA. • A five-gene MYC network signature stratifies BLCA risk and predicts therapy response. • High POLR3G links to immunosuppression and resistance to chemo/immunotherapy in BLCA. • POLR3G may regulate bladder cancer cell senescence via p53 signaling. The MYC oncogene is a central driver of bladder cancer (BLCA) pathogenesis. However, the systematic role of its co-expressed gene network in BLCA progression, tumor microenvironment remodeling, and therapeutic response remains largely unexplored. Using the TCGA-BLCA dataset, we identified MYC co-expressed genes via the LinkedOmics platform. Consensus clustering was employed to define molecular subtypes based on this network. A prognostic signature was constructed using LASSO Cox regression. Immune infiltration was assessed with the xCell and TIP algorithms, and therapy responses were predicted via TIDE and drug sensitivity analysis. POLR3G's expression was validated in clinical samples using immunohistochemistry. Consensus clustering stratified BLCA patients into two distinct subtypes with significant survival differences, linked to NF-κB/IL-17/JAK-STAT and PPAR signaling pathways, respectively. A robust five-gene prognostic signature was developed. The high-risk group, characterized by an immunosuppressive microenvironment and elevated immune checkpoint expression, demonstrated poorer survival and predicted resistance to immune checkpoint blockade. Among the signature genes, POLR3G emerged as the most powerful independent prognostic factor. Furthermore, POLR3G expression was correlated with resistance to both chemotherapy and immunotherapy. Its upregulation in BLCA tissues was confirmed experimentally. Our study reveals that the MYC co-expression network is critical for BLCA heterogeneity. We established a novel prognostic signature with significant clinical utility for risk stratification and therapy guidance. POLR3G is highlighted as a pivotal oncogene associated with BLCA cell senescence and treatment resistance, thereby representing a promising new biomarker and therapeutic target.