Abstract
BackgroundDNA polymerase delta 1 catalytic subunit (POLD1) plays a key role in DNA replication and damage repair. A defective DNA proofreading function caused by POLD1 mutation contributes to carcinogenesis, while POLD1 overexpression predicts poor prognosis in cancers. However, the effect of POLD1 in hepatocellular carcinoma (HCC) is not well-understood.MethodsExpression patterns of POLD1 were evaluated in TCGA and the HPA databases. Kaplan-Meier curves and Cox regression were used to examine the prognostic value of POLD1. The prognostic and predictive value of POLD1 was further validated by another independent cohort from ICGC database. The influences of DNA copy number variation, methylation and miRNA on POLD1 mRNA expression were examined. The correlation between infiltrating immune cells and POLD1 expression was analyzed. GO and KEGG enrichment analyses were performed to detect biological pathways associated with POLD1 expression in HCC.ResultsPOLD1 was overexpressed in HCC (n = 369) compared with adjacent normal liver (n = 50). POLD1 upregulation was significantly correlated with positive serum AFP and advanced TNM stage. Kaplan–Meier and multivariate analyses suggested that POLD1 overexpression predicts poor prognosis in HCC. DNA copy gain, low POLD1 methylation, and miR‑139-3p downregulation were associated with POLD1 overexpression. Besides, POLD1 expression was associated with the infiltration levels of dendritic cell, macrophage, B cell, and CD4 + T cell in HCC. Functional enrichment analysis suggested “DNA replication”, “mismatch repair” and “cell cycle” pathways might be involved in the effect of POLD1 on HCC pathogenesis. Additionally, POLD1 mRNA expression was significantly associated with tumor mutation burden, microsatellite instability, and prognosis in various tumors.ConclusionsPOLD1 may be a potential prognostic marker and promising therapeutic target in HCC.
Highlights
DNA polymerase delta 1 catalytic subunit (POLD1) plays a key role in DNA replication and damage repair
The Kyoto encyclopedia ofgenes and genomes (KEGG) analysis demonstrated “DNA replication”, “nucleotide excision repair” and “cell cycle” pathways might be involved in the effect of POLD1 on hepatocellular carcinoma (HCC) pathogenesis (Fig. 9 C)
We identified the top 100 POLD1-correlated genes and 50 experimentally determined POLD1-binding proteins, functional enrichment analysis demonstrated “DNA replication”, “mismatch repair” and “cell cycle” pathways might be involved in the effect of POLD1 on HCC pathogenesis
Summary
DNA polymerase delta 1 catalytic subunit (POLD1) plays a key role in DNA replication and damage repair. The effect of POLD1 in hepatocellular carcinoma (HCC) is not well-understood. Hepatocellular carcinoma (HCC) is one of the most common primary tumors worldwide [1]. It is urgent to further explore the underlying mechanisms of HCC carcinogenesis and development, which will contribute to the detection of novel promising prognostic and therapeutic targets. DNA polymerase delta 1 catalytic subunit (POLD1) encodes the 125-kDa catalytic subunit and provides the essential catalytic activity of DNA polymerase delta, which exhibits both DNA polymerase and 3’ to 5’ exodeoxyribonuclease activity, and plays a crucial role in DNA replication, DNA damage repair, cell growth and differentiation [2, 3]. Previous studies suggested that POLD1 was upregulated in HCC and breast cancer, and
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