Leveraging hypoxia-related genes signature for predicting the prognosis of bladder cancer

Hypoxia is common in solid tumors, facilitating tumor growth and treatment resistance, and is crucial for optimizing patient outcomes, but research on the mechanism of hypoxia in bladder cancer (BC) remains limited. This study aims to explore the functional role of hypoxia-related genes (HRGs) in BC.

The HRGs were obtained from GeneCards, and the hypoxia score in BC patients was evaluated by single-sample gene set enrichment analysis (ssGSEA). The prognostic risk model was constructed using differentially expressed prognostic HRGs, and assessed via time-dependent receiver operating characteristic (ROC) curves, Kaplan-Meier (KM) curve, and nomogram analysis. Differential features between high- and low-risk groups were analyzed, including clinical characteristics, biological functions, mutation profiles, immune infiltration, and drug sensitivity. We measured the expression of hub genes in vitro via quantitative real-time polymerase chain reaction (qRT-PCR), assessed their interactions with special herbal monomers, and evaluated the developmental trajectories using single-cell sequencing data of BC.

The hypoxia score system was proven effective in BC diagnosis and prognostic prediction based on ROC and KM analyses. The prognostic risk model was constructed with JUN, MYC, EGFR, and SLC2A1, and effectively stratified BC risk. Numerous mutations, especially the frequent TP53, occurred in both risk groups. Besides, the high-risk group exhibited more immune cell infiltration. Moreover, solasonine and rhein were predicted to exhibit well binding affinity for hub genes, especially EGFR and SLC2A1. Additionally, a predominance of malignant epithelial cells in BC was confirmed using single-cell data, with significant variation in JUN along the developmental trajectory and an increase of MYC at developmental endpoint, highlighting their critical roles in BC progression.

We developed a novel prognostic risk model as an independent predictor for BC patients, which offers insights into immune microenvironment and carcinogenesis mechanisms of BC. Analyzing mutation patterns, drug sensitivities, and the developmental trajectories of genes within this model would be helpful for refining therapeutic strategies.