Abstract Background Bladder cancer affects men and women differently: men are diagnosed more frequently, but women often present with advanced disease and have worse survival. The biological mechanisms underlying these disparities remain unclear. This study aimed to identify sex-specific molecular features and regulatory interactions that shape tumor biology and outcomes. Methods We performed an integrative multi-omics analysis combining bulk messenger RNA and microRNA expression, survival modeling, and single-cell transcriptomic profiling. Data were obtained from The Cancer Genome Atlas, Gene Expression Omnibus, and the Genome Sequence Archive. Differential expression analyses were conducted separately in tumors and in normal samples to compare males and females. Experimentally validated microRNA–mRNA target pairs were tested for correlation, and survival associations were evaluated using Kaplan–Meier and Cox models. Single-cell RNA-seq data were analyzed to assess sex-biased expression across tumor and immune cell populations. Results We identified 48 tumor-specific sex-biased microRNAs and 456 tumor-specific sex-biased genes, the majority located on autosomes rather than sex chromosomes. Correlation analysis revealed 82 experimentally supported, negatively correlated microRNA–mRNA pairs, including 63 discordant pairs with opposite sex-biased expression, suggesting sex-specific regulatory interactions. Several of these features were significantly associated with overall survival in a sex-dependent manner. For example, the male-upregulated microRNA miR-1270 showed repression of the female-biased targets CYP26B1 and FAM180A, both of which were associated with poor survival, highlighting potential prognostic and therapeutic relevance. Single-cell analysis revealed widespread sex-biased expression across epithelial, stromal, and immune cells, with female tumors showing stronger signals in stromal and immune compartments, which may contribute to the more aggressive clinical course observed in females. Conclusions Our findings indicate that sex disparities in bladder cancer are largely driven by post-transcriptional regulation of autosomal genes, rather than sex chromosome dosage. By linking sex-biased microRNAs, target genes, and patient survival with cell type–specific expression, this study provides new insight into the biological basis of sex differences in bladder cancer. These results underscore the importance of incorporating sex as a critical variable in biomarker development, therapeutic targeting, and clinical trial design.
Wang et al. (Fri,) studied this question.