Downregulation of PDIA4 inhibits proliferation and migration in human oral squamous cell carcinoma

TL;DR

This study shows that PDIA4 promotes oral cancer growth and poor outcomes, suggesting it could be a new target for treatment.

Contribution

The study identifies PDIA4 as a novel prognostic biomarker and therapeutic target in oral squamous cell carcinoma.

Findings

High PDIA4 expression correlates with poor prognosis and reduced immunotherapy response in oral cancer patients.

Downregulating PDIA4 inhibits cancer cell proliferation and migration via the FoxO1/p21CIP1 pathway.

PDIA4 levels are negatively linked to CD4 and CD8 T cell infiltration but positively linked to M0 macrophages and regulatory T cells.

Abstract

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.

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.

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.

These findings suggest that PDIA4 may potentially serve as both a prognostic biomarker and a therapeutic target for OSCC patients.

The online version contains supplementary material available at 10.1186/s41065-025-00594-2.

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