Identification of hub genes and potential molecular mechanisms related to chemotherapy sensitivity in bladder cancer: A Comprehensive Analysis

Abstract Chemotherapy resistance drives bladder cancer (BC) recurrence and metastasis, but the biomarkers and mechanisms of chemotherapy sensitivity are not fully known. We identified differentially expressed genes (DEGs) in chemo-resistant and -sensitive BC patients from TCGA and GEO databases. Analyses like GO, KEGG, random survival forest were conducted. We studied the relationships of hub genes with immune cell infiltration, pathways, drug sensitivity, prognosis, regulation, and cellular heterogeneity using multiple methods. A total of 4042 up-regulated and 1355 down-regulated DEGs were included in the analysis. Four hubs, RNF19A, PCGF5, UNC5CL, and CCDC146, were identified and linked to tumor immune infiltration, immune-related genes, sensitivity to chemotherapeutic drugs, and the expression of disease-related genes like APC and EGFR. GSVA and GSEA analysis revealed varying expression levels of these genes impacting cancer-related signaling pathways. A nomogram and calibration curves based on these hub genes showed excellent prognosis predictive performance. We identified key binding motifs and transcription factors for hub genes using RcisTarget. Our mRNA-miRNA regulatory network and single cell analysis revealed cellular heterogeneity in hub gene expression. Therefore, up-regulation of RNF19A, PCGF5, UNC5CL, and CCDC146 in BC is associated with chemotherapy response and various cellular functions, making them potential predictive biomarkers for chemotherapy sensitivity and prognosis.