1-Hydroxypyrene Promotes Bladder Cancer Progression and Tumor-Associated Immunosuppression via MIF

Vollständiger Abstract

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This study examined how 1-hydroxypyrene (1-OHP) affects bladder cancer (BCa) progression and tumor-associated immunosuppression. Public transcriptomic data and target-prediction databases were used to screen for targets related to 1-OHP and BCa. Machine learning was then used to narrow down the candidate genes. Molecular docking and single-cell RNA sequencing were also used to examine the selected targets and related pathways. The role of the main target was tested in vitro. CCK-8, colony formation, EdU, and Transwell assays were used to assess cell growth, migration, and invasion. Protein expression was examined by Western blotting. A tumor cell–CD8+ T-cell co-culture system was used to evaluate changes in CD8+ T-cell function. We identified 29 targets shared by 1-OHP and BCa. Machine learning further narrowed these targets to six genes, and macrophage migration inhibitory factor (MIF) was chosen for experimental validation. Treatment with 1-OHP increased BCa cell viability, proliferation, migration, and invasion. Silencing MIF partly reduced these effects. 1-OHP also increased MIF and CD74/CD44 expression and enhanced PI3K/AKT/mTOR signaling. These changes were reduced after MIF silencing. In the co-culture system, 1-OHP-treated BCa cells reduced CD8+ T-cell proliferation and function. Ki67, GZMB, and IFNG levels were decreased. MIF knockdown partly reversed these changes. Collectively, our findings show that 1-OHP promotes bladder cancer progression and tumor-associated immunosuppression, at least in part, through a MIF-dependent mechanism. By linking environmental exposure to activation of the CD74/CD44–PI3K/AKT/mTOR axis and impaired CD8+ T-cell function, our study provides new insight into the molecular basis of environmentally associated bladder carcinogenesis.