POLD3 knockdown effects on low-grade glioma: insights from bioinformatics and experimental validation

Lower-grade glioma (LGG) is a common primary brain tumor with potential progression to glioblastoma. Its development is closely linked to DNA damage repair. DNA polymerase delta subunit 3 (POLD3), a subunit of the DNA polymerase δ complex, participates in DNA replication and repair. POLD3 may act as a therapeutic target and prognostic biomarker in LGG.

We collected primary data from The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), the Tumor Immune Estimation Resource (TIMER), and Gene Set Enrichment Analysis (GSEA). The CGGA dataset included messenger RNA (mRNA) sequencing and clinical data from 403 LGG cases; its microarray subset contained 142 additional cases. The TCGA dataset provided clinical data for 503 LGG cases. Employing bioinformatics tools, we investigated the correlation of POLD3 expression with the clinical characteristics, pathological features, survival outcomes, and tumor immune microenvironment in LGG. Subsequent functional validation of POLD3's impact in LGG was performed using both cellular and animal models.

Integrative analysis combining bioinformatics and experimental approaches revealed significant POLD3 overexpression in LGG. Elevated POLD3 levels exhibited significant associations with distinct clinicopathological features, altered immune cell infiltration profiles, and adverse clinical outcomes. Functionally, POLD3 was demonstrated to drive LGG cell proliferation, invasion, and modulate the tumor microenvironment.

This study establishes POLD3 as a critical molecular determinant in LGG pathogenesis. Our findings position POLD3 as a promising multifaceted target, with significant implications for advancing LGG diagnostics, therapeutic development, immune modulation strategies, and prognostic assessment, thereby providing a fresh conceptual framework for understanding and managing this tumor.