Abstract Title Comparative Analysis of PRDX Expression in Bladder Urothelial Carcinoma and Decoding Its Prognostic Value

Background Bladder urothelial carcinoma (BLCA) is one of the most common types of urologic malignancies that disproportionately affects older males and is projected to double by 2040. Oxidative stress is a common hallmark of cancer, resulting from an imbalance between the overproduction of reactive oxygen species (ROS) and dysfunctional antioxidant defenses. Peroxiredoxin (PRDX1-6) are a family of antioxidant enzymes with each possessing unique biological roles. However, their contributions in cancer progression, immune modulation, and prognostic qualities in patients with BLCA remain unclear. This study investigates the association between PRDXs expression and their impact on genomic instability, tumor immune microenvironment, and tumor characteristics in BLCA.

Methods Clinical information and RNA sequencing data of the PRDX genes were acquired from The Cancer Genome Atlas (TCGA). Samples were grouped by PRDX expression levels using their z-score relative to all samples (n = 411). An analysis was conducted to assess the relationship between PRDXs expression levels to genomic instability metrics (aneuploidy score, mutation score, TMB, MSI), tumor immune microenvironment (immune score, stromal score, estimate score), and expression of innate immune and checkpoint genes. Kaplan–Meier survival analysis and ROC curves were also generated to evaluate their prognostic relevance.

Results Overexpression of PRDX1, PRDX4, and PRDX5 were significantly associated with genomic instability. While the overexpression of PRDX2, PRDX4, and PRDX6 were significantly associated with tumor immune microenvironment. The heatmap analysis for innate immune genes showed that PRDX4 and PRDX6 exhibited a hot immune phenotype with high expression of immune checkpoint genes (PDCD1LG2), whereas PRDX2 and PRDX3 exhibited colder immune profiles with downregulation of immune checkpoints. Notably, the overexpression of PRDX6 was associated with poor prognosis and more advanced tumor characteristics. In contrast, the overexpression of PRDX1 was also linked to reduced overall survival and a colder immune phenotype, suggesting potential immune evasion.

Conclusion PRDX6 was linked to poor prognosis as evidenced by its reduced survival outcome and hot immune phenotype, suggesting a role in driving tumor progression. PRDX4 emerged as a gene of interest due to its impact on genomic instability and tumor immune microenvironment. In contrast, PRDX2 overexpression were associated with more advanced tumor stage and size, but not a significant impact on overall survival suggesting a role in tumor growth dynamics rather survival. Our findings may have important clinical implications for utilizing PRDXs as a potential prognostic biomarker to stratify BLCA patients and as a target to enhance immunotherapy response in BLCA. Future studies should validate findings and explore the role of PRDXs as useful biomarkers when combined with other biomarkers to improve BLCA prognosis.