Integrative analysis of the PSMA family identifies PSMA6 as an adverse prognostic biomarker promoting bladder cancer cell proliferation.

BACKGROUND: Proteasome subunit alpha members (PSMAs) are reported to be involved in diverse biological processes, and mounting evidence indicates that PSMAs have been implicated in the carcinogenesis of various malignancies. Nevertheless, there is a scarcity of reports on the expression, prognostic significance, and potential functions of the PSMA family in bladder cancer (BLCA). METHODS: We utilized the TCGA, GEO, TIMER, UALCAN, and HPA databases to evaluate the expression of PSMAs in BLCA. Survival analyses were performed using Kaplan-Meier methods. The validation of PSMA6 dysregulation in human BLCA samples encompassed western blotting and immunohistochemistry. For the enrichment of biological processes, we applied Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analyses (GSEA). Subsequent analyses involved the exploration of correlations between gene expression and Immune-related effects. In-depth investigations into the role of PSMA6 in BLCA were conducted through both in vitro and in vivo experiments. RESULTS: We demonstrated that PSMA6 was upregulated among PSMAs in BLCA, and overexpression of PSMA6 was associated with unfavorable prognosis and tumor malignancy. Enrichment analyses disclosed the involvement of PSMA6 in immune-related activities within the tumor microenvironment. Furthermore, the expression of PSMA6 was closely correlated with tumor-infiltrating immune cells (TICs) and immune checkpoints (ICPs). Besides, we also revealed that BLCA patients with high PSMA6 expression would have better immunotherapy response. Functional studies demonstrated that PSMA6 knockdown suppressed BLCA cell proliferation in vitro and in vivo. CONCLUSIONS: Our findings suggested that PSMA6 might function as an unfavorable prognostic biomarker, fostering BLCA cell proliferation, while also potentially serving as a predictive indicator for the efficacy of immunotherapy in BLCA patients.