Highlights
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PSMD14/NCL/YAP1 axis linked to PD-L1-mediated immune evasion in BCa.
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Humanized mouse models advocated for PSMD14 immune microenvironment validation.
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Proposed PSMD14-siRNA nanotherapy via clinically advanced delivery systems.
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Integrated TCGA-spatial analysis revealing PSMD14′s role in BCa.
Dear Editor,
We are writing to comment on the recent article by Wu et al., titled "Prognostic biomarker PSMD14 facilitates bladder cancer tumorigenesis and progression by regulating Nucleolin-YAP1 axis [1]," published in Translational Oncology. This comprehensive study elucidates the role of PSMD14 as a deubiquitinating enzyme that stabilizes nucleolin (NCL), thereby enhancing YAP1 mRNA stability and driving bladder cancer (BCa) proliferation, metastasis, and cisplatin resistance. The authors provided insights into how the PSMD14/NCL/YAP1 axis contributes to the malignant phenotype of BCa through detailed analysis.
PSMD14 is overexpressed in several cancer types, including colon cancer [2] and breast cancer [3], promoting tumor progression and therapy resistance through its modulation of protein deubiquitination. The study by Wu et al. elucidated the oncogenic role of PSMD14 in BCa and provided a potential treatment strategy for BCa.
Although excellent, the study by Wu et al. has limitations. The YAP1-PD-L1 axis has been established as a promoter of immune evasion in colorectal cancer [4], melanoma [5], and ovarian cancer [6]. Moreover, Yu et al. demonstrated that PD-L1 mediates immune evasion in BCa [7], influencing the tumor immune microenvironment (Supplementary Table S1). Notably, Wu et al. did not address the potential role of the PSMD14/NCL/YAP1 axis in regulating PD-L1 expression or the tumor immune microenvironment. Addressing this gap, our spatial analysis suggests PSMD14-enriched fibroblasts may shape an immunosuppressive microenvironment in BCa (Fig. 1, Supplementary Figures S1-S6).
Fig. 1.
Exploratory analysis of PSMD14 expression and immune microenvironment in BCa. (A) PSMD14 expression negatively correlates with Tregs (R²=0.053, p = 1.4e-06) and positively correlates with M0 macrophages (R²=0.015, p = 0.010) in TCGA-BLCA cohort; (B) PSMD14 spatially enriched in fibroblast-rich tumor core in Spatial transcriptomics (GSM8707234); (C) Co-localization of fibroblast density and macrophage recruitment with PSMD14; (D) Conserved PSMD14 expression patterns across all sections (GSM8707234, GSM8707235, GSM8707236).
In this study, the authors used subcutaneous xenograft and tail vein injection models in vivo. These models may not fully recapitulate the complexity of the BCa microenvironment. This complexity is essential for the accurate analysis of the role of PSMD14. Wang et al. investigated PD-1-targeted immunotherapy mechanisms in BCa using a humanized mouse model [8]. The humanized mouse model may not fully capture the complexity of the BCa microenvironment, essential for the accurate analysis of PSMD14′s role in BCa.
Nanoparticle-delivered siRNA technology significantly inhibits proliferation and metastasis in BCa [9], though PSMD14-specific siRNA delivery has not been reported. Given that this technology has advanced into clinical application [10], its potential has been verified. Future studies should investigate the feasibility of nanoparticle-delivered PSMD14 siRNA in mouse models. Long-term safety and efficacy monitoring is essential before their administration to patients.
Sincerely.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Availability of data and materials
Publicly available datasets were analyzed in this study: TCGA-BLCA cohort was obtained from GDC Portal (https://portal.gdc.cancer.gov/); Immune infiltration profiles were calculated using CIBERSORT (LM22 signature). The data can be found in the GEO database (https://www.ncbi.nlm.nih.gov/geo/), Single-cell RNA-seq data (GSE267718: GSM8273667, GSM8273670); Spatial transcriptomics (GSE285715: GSM8707234-GSM8707236).
Funding
This study was funded by the Dalian Life and Health Field Guidance Plan (2024ZDJH01PT068) and the 2025 Liaoning Provincial Natural Science Foundation.
CRediT authorship contribution statement
Yongzheng Han: Writing – original draft. Chang Liu: Writing – review & editing. Guangzhen Wu: Writing – review & editing, Supervision, Funding acquisition.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
Not applicable.
Footnotes
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.tranon.2025.102498.
Contributor Information
Chang Liu, Email: liuchang9011@aliyun.com.
Guangzhen Wu, Email: wuguangzhen@firsthosp-dmu.com.
Appendix. Supplementary materials
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Publicly available datasets were analyzed in this study: TCGA-BLCA cohort was obtained from GDC Portal (https://portal.gdc.cancer.gov/); Immune infiltration profiles were calculated using CIBERSORT (LM22 signature). The data can be found in the GEO database (https://www.ncbi.nlm.nih.gov/geo/), Single-cell RNA-seq data (GSE267718: GSM8273667, GSM8273670); Spatial transcriptomics (GSE285715: GSM8707234-GSM8707236).