Integrated multi-omics analysis identifies DARS2, MRTO4, and MRPL37 as novel biomarkers and potential therapeutic targets for bladder cancer.

BACKGROUND: Bladder cancer (BC) is the predominant malignant tumor in the urinary system globally, with its intricate molecular features greatly influencing patient outcomes and treatment response.Identifying novel biomarkers and therapeutic targets is essential for improving patient management.

METHODS: This study utilized advanced bioinformatics techniques to analyze data from multiple public databases, including The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), IEU OpenGWAS project, eQTLGen, FinnGen, and DepMap. The analytical framework integrates the limma package for the identification of differentially expressed genes (DEGs), employs Weighted Gene Co-expression Network Analysis (WGCNA) to ascertain genes associated with BC, utilizes Mfuzz-based clustering to categorize gene expression profiles, implements univariate Cox regression modeling, conducts Kaplan-Meier (KM) survival analysis for the selection of prognostic genes, and applies Mendelian Randomization (MR) analysis to ascertain core genes. The expression patterns of core genes were verified through single - cell RNA sequencing (scRNA - seq) analysis. Receiver operating characteristic (ROC) analysis was carried out to evaluate the diagnostic and prognostic capacities of the core genes. Consensus clustering analysis further confirmed the risk stratification potential of these genes. Gene Set Enrichment Analysis (GSEA) was applied to explore the potential mechanisms of these genes in BC, the associations between these genes and the immune microenvironment, and their predictive effectiveness for immunotherapy response. Moreover, a web - based nomogram tool was constructed to predict patient prognosis. Ultimately, MR mediation analysis was utilized to further probe into the mediating mechanism of immune cells in the progression of core genes and BC.

RESULTS: Comprehensive analysis identified DARS2, MRTO4, and MRPL37 as core genes in BC. The expression of these genes was notably elevated in neoplastic tissues compared to that in normal bladder epithelia, with a progressive escalation in expression levels concomitant with the advancement of tumor stage. Analyses employing Receiver Operating Characteristic (ROC) curves and consensus clustering corroborated their robust potential for diagnostic and prognostic purposes. These genes potentially facilitate BC progression via the oxidative phosphorylation (OXPHOS) and Myc target pathways, and are significantly associated with the infiltration of immune cells such as activated CD4 T cells, effector memory CD4 T cells, and immature dendritic cells (iDCs). Furthermore, the developed online nomogram tool exhibited high accuracy. Finally, the results of the mediation analysis confirmed that MRPL37 promotes the occurrence and development of BC via HLA-DR⁺ CD4⁺ T cells (βmed = 0.083, βmedp = 36.3%, p = 0.046).

CONCLUSION: This research underscores the substantial functions of DARS2, MRTO4, and MRPL37 in the development of BC and their potential as therapeutic targets, offering a foundation for future investigations and the development of targeted therapies.