Abstract
Background
Non-small cell lung cancer (NSCLC) contributes to the vast majority of cancer-related deaths. Proteasome 26S subunit, non-ATPase 12 (PSMD12), a subunit of 26S proteasome complex, is known to play the tumor-promoting role in several types of cancer but its function in NSCLC remains elusive.
Objective
To explore the role and underlying mechanisms of PSMD12 in NSCLC.
Methods
The PSMD12 expression in human normal lung epithelial cell line (BEAS-2B) and four NSCLC cell lines (A549, NCI-H1299, NCI-H1975, Calu-1) were determined by qRT-PCR and western blot. Malignant phenotypes of NSCLC cells were detected by CCK-8, EdU staining, immunofluorescence staining for E-cadherin, flow cytometry, and Transwell assays to assess cell viability, proliferation, epithelial-mesenchymal transition (EMT), apoptosis, migration and invasion. Dual luciferase assay was used to verify the regulatory role of transcription factor on the promoter.
Results
We identified the upregulation of PSMD12 in NSCLC tissues based on the GEO datasets, which further verified in NSCLC and BEAS-2B cell lines. PSMD12 knockdown significantly suppressed malignant behaviors of NSCLC cells, including cell growth, invasion, and migration, while PSMD12 overexpression presented the opposite effects. Interestingly, we found that PSMD12 upregulated the tumor-promoting factor TrxR1 mRNA expression. For its potential mechanisms, we demonstrated that PSMD12 elevated transcription factor Nrf2 protein level and promoted Nrf2 nuclear translocation. And Nrf2 further increased TrxR1 promoter activity and enhanced TrxR1 transcription. Meanwhile, we proved that TrxR1 overexpression erased the inhibitory effect of PSMD12 knockdown.
Conclusion
PSMD12 promotes NSCLC progression by activating the Nrf2/TrxR1 pathway, providing a novel prognostic and therapeutic target for NSCLC treatment.
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Data availability
The data generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Funding
This study was supported by the Natural Science Foundation of Ningxia Province (under Grant 2022AAC03352).
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Conceptualization: all authors. Methodology: J.L. and S.M. Formal analysis and investigation: X.W. and J.D. Writing - original draft preparation: J.L. and F.M. Writing - review and editing: S.M.
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Supplementary Material Table S1: Primer sequences of specific genes
Supplementary Material Table S2: Information of antibodies used for western blot analysis
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Lv, J., Ma, S., Wang, X. et al. PSMD12 promotes non-small cell lung cancer progression through activating the Nrf2/TrxR1 pathway. Genes Genom 46, 263–277 (2024). https://doi.org/10.1007/s13258-023-01484-5
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DOI: https://doi.org/10.1007/s13258-023-01484-5