Downregulation of PDIA4 inhibits proliferation and migration in human oral squamous cell carcinoma
Yue Hu1,2, Wei Zhang1, Fuyu Zhang1,2
1Department of Radiation Oncology, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, No.42 Zhaowuda Road, Saihan District, Hohhot, Inner Mongolia Autonomous Region, 010020, China.
Background:
Protein disulfide isomerase family A member 4 (PDIA4), a member of the protein disulfide isomerase family, has been associated with the progression of cancer. Nevertheless, its specific function in oral squamous cell carcinoma (OSCC) is not yet well understood.
Methods:
To assess the prognostic significance and functional profile of the PDIA4, survival analysis and GSEA were conducted. Additionally, we examined the differences in immune infiltration and immunotherapy response between groups with low and high expression levels of PDIA4. Subsequently, RT-qPCR and western blot assays were employed to verify PDIA4 expression in OSCC tissues. The functional implications of PDIA4 in OSCC cells were also investigated.
Results:
Analysis of the TCGA-OSCC dataset revealed a notable increase in PDIA4 expression in OSCC tissues, as verified by RT-qPCR and western blot analyses. Additionally, elevated PDIA4 levels were associated with poor prognosis in OSCC patients. GSEA results showed that the cellular senescence, FoxO and Hippo signaling pathways were remarkably inactivated in the high PDIA4 expression group. Moreover, a negative correlation was observed between PDIA4 levels and the infiltration of CD4, CD8 and natural killer T cells. Conversely, a positive correlation was observed between PDIA4 levels and M0 macrophage and regulatory T cell infiltration. Meanwhile, OSCC patients exhibiting elevated PDIA4 expression demonstrated elevated TIDE scores, implying a reduced responsiveness to immunotherapy in these individuals. Functionally, the suppression of PDIA4 significantly suppressed both proliferation and migration of OSCC cells, potentially through activating the FoxO1/p21CIP1 pathway.
Conclusion:
These findings suggest that PDIA4 may potentially serve as both a prognostic biomarker and a therapeutic target for OSCC patients.
Insights
Protein disulfide isomerase family A member 4 (PDIA4) is elevated in oral squamous cell carcinoma (OSCC), correlating with poor prognosis and altered immune infiltration. PDIA4 inhibition suppressed OSCC cell growth, suggesting its potential as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Protein disulfide isomerase family A member 4 (PDIA4) is implicated in cancer progression.
- Its specific role in oral squamous cell carcinoma (OSCC) remains unclear.
Purpose of the Study:
- To investigate the prognostic significance and functional role of PDIA4 in OSCC.
- To explore PDIA4's impact on immune infiltration and immunotherapy response in OSCC.
Main Methods:
- Survival analysis and Gene Set Enrichment Analysis (GSEA) were performed.
- Immune infiltration and immunotherapy response were assessed.
- PDIA4 expression was validated using RT-qPCR and Western blot; functional assays were conducted.
Main Results:
- PDIA4 expression is significantly increased in OSCC tissues and linked to poorer patient prognosis.
- High PDIA4 expression correlated with inactivated cellular senescence, FoxO, and Hippo pathways, and altered immune cell infiltration (decreased CD4+, CD8+, NK T cells; increased M0 macrophages, regulatory T cells).
- PDIA4 suppression inhibited OSCC cell proliferation and migration, potentially via the FoxO1/p21CIP1 pathway, and was associated with reduced immunotherapy response.
Conclusions:
- PDIA4 serves as a potential prognostic biomarker in OSCC.
- PDIA4 represents a promising therapeutic target for OSCC treatment.
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