PSMD2-Mediated MAPK Signaling Promotes Bladder Cancer Development and Immune Microenvironment Remodeling.

OBJECTIVES: Bladder cancer (BCa) progression is closely linked to the immune microenvironment. However, the key molecules that regulate this microenvironment and their specific mechanisms remain poorly understood. This study aims to identify a key molecule and elucidate its mechanisms, providing a theoretical basis for identifying novel therapeutic targets. METHODS: Immune microenvironment-related genes in BCa were identified using The Cancer Genome Atlas and Shanghai Tenth People's Hospital datasets. Proteasome 26S subunit non-ATPase 2 (PSMD2) expression was validated via quantitative polymerase chain reaction (qPCR), Western blot (WB) analysis, and immunofluorescence (IF). In vitro and in vivo experiments confirmed the role of PSMD2 in cell proliferation, invasion, and migration. Kyoto encyclopedia of genes and genomes (KEGG) and Gene Ontology (GO) analyses were conducted to assess PSMD2's influence on immune microenvironment remodeling. A pathomics model predicted PSMD2 expression in patients with BCa. RESULTS: PSMD2 was identified as a critical factor in BCa, with high expression correlating with poor prognosis and tumor progression. Mechanistically, PSMD2 enhances malignancy by promoting mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) phosphorylation within the mitogen-activated protein kinase (MAPK) signaling pathway. Combined bioinformatics and experimental analyses reveal that PSMD2 downregulates chemokine (C-X-C motif) ligand 14 (CXCL14) expression and secretion via the MAPK pathway, thereby remodeling the immune microenvironment and driving tumor progression. Pathomics analysis further supports the potential of PSMD2 expression as a predictive marker in BCa tissues. CONCLUSION: PSMD2 is overexpressed in BCa and significantly correlates with poor prognosis and tumor progression. It promotes malignant development and immune microenvironment remodeling through the MAPK pathway. Pathological analysis can predict PSMD2 expression, offering valuable insights into immunotherapy responses and survival outcomes.