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ARTICLE

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

Shuwen Sun1,2,3,4,#, Jingcheng Zhang1,2,3,#, Zongtai Zheng5,#, Yajuan Hao1,3, Tianyuan Xu1,2,3, Ji Liu1,3, Liang Sun2, Aimin Wang2, Yadong Guo1,3, Shiyu Mao1,3, Xu Zhang6, Yunfei Xu1,3,*, Yifan Chen1,2,3,*, Yang Yan1,2,3,*
1 Department of Urology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
2 Department of Urology, Bengbu First People’s Hospital, Bengbu, 233000, China
3 Urologic Cancer Institute, School of Medicine, Tongji University, Shanghai, 200072, China
4 Department of Nuclear Medicine, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
5 Department of Urology, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, 510317, China
6 Bio-X Institutes (Key Laboratory for the Genetics of Development and Neuropsychiatric Disorders), Shanghai Jiao Tong University, Shanghai, 200240, China
* Corresponding Author: Yunfei Xu. Email: email; Yifan Chen. Email: email; Yang Yan. Email: email
# These authors contributed equally to this work
(This article belongs to the Special Issue: Targeting the Tumor Microenvironment: Emerging Insights into Cancer Progression and Therapeutics)

Oncology Research https://doi.org/10.32604/or.2025.072373

Received 25 August 2025; Accepted 22 December 2025; Published online 14 January 2026

Abstract

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.

Graphical Abstract

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

Keywords

Bladder cancer (BCa); proteasome 26S subunit non-ATPase 2 (PSMD2); C-X-C motif chemokine ligand 14 (CXCL14); immune infiltration

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