Elevated DNA Polymerase Delta 1 Expression Correlates With Tumor Progression and Immunosuppressive Tumor Microenvironment in Hepatocellular Carcinoma

Abstract

Background and ObjectiveHepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and the DNA polymerase delta (POLD) family is significantly related to cancer prognosis. This study aimed to explore the significance of the POLD family in HCC via the DNA damage repair (DDR) pathway.MethodsData mining was conducted using bioinformatics methods. RNA sequencing and clinicopathological data were collected from The Cancer Genome Atlas, GTEx database and the Gumz Renal cohort. Statistical analyses were also performed in cancer samples (n>12,000) and the Affiliated Hospital of Youjiang Medical University for Nationalities (AHYMUN, n=107) cohort.ResultsThe POLD family (POLD1–4) was identified as the most important functional component of the DDR pathway. Based on the analysis of independent cohorts, we found significantly elevated POLD expression in HCC compared with normal tissues. Second, we investigated the prognostic implication of elevated POLD1 expression in HCC and pan-cancers, revealing that increased POLD1 levels were correlated to worse prognoses for HCC patients. Additionally, we identified 11 hub proteins interacting closely with POLD proteins in base excision repair, protein-DNA complex and mismatch repair signaling pathways. Moreover, POLD1 mutation functioned as an independent biomarker to predict the benefit of targeted treatment. Importantly, POLD1 expression was associated with immune checkpoint molecules, including CD274, CD80, CD86, CTLA4, PDCD1 and TCGIT, and facilitated an immune-excluded tumor microenvironment. Additionally, we confirmed that elevated POLD1 expression was closely correlated with the aggressive progression and poor prognosis of HCC in the real-world AHYMUN cohort.ConclusionWe identified a significant association between elevated POLD1 expression and poor patient survival and immune-excluded tumor microenvironment of HCC. Together, these findings indicate that POLD1 provides a valuable biomarker to guide the molecular diagnosis and development of novel targeted therapeutic strategies for HCC patients.

Increased DNA Polymerase Epsilon Catalytic Subunit Expression Predicts Tumor Progression and Modulates Tumor Microenvironment of Hepatocellular Carcinoma

“…International Publisher malignant tumors in humans, ranking third in the cause of cancer-related death [3], and the majority of patients are diagnosed at an advanced stage [4].…”

“…Previously, various immunotherapy methods have been developed, which mainly rely on immune cells within or outside of the tumor microenvironment (TME) to specifically target and attack cancer cells [9]. Also, immune checkpoint inhibitor therapy has been employed, and hub genes like POLE, DK1, CDC20 and CCNB1 have been found as biomarkers of progression in HCC patients [10][11][12]. However, the immune microenvironment of HCC has not been fully explored [13].…”

Integrated machine learning and bioinformatic analyses used to construct a copper-induced cell death-related classifier for prognosis and immunotherapeutic response of hepatocellular carcinoma patients

“…CTLA-4 and PD-1/PD-L1 are primary targets for immune checkpoint inhibitors (ICIs), some of which are currently approved or in clinical trials for HCC ( Zhang et al, 2017 ; Seidel et al, 2018 ). Because of tumor heterogeneity, TME alteration, development of drug resistance, hypervascularity, hypoxia, and severe side effects, treatment of HCC with ICIs or ACT alone failed to achieve primary clinical endpoints, including a reduction in tumor size and antitumor response ( Altekruse et al, 2014 ; Zhao et al, 2021a ). Therefore, developing markers is crucial which may help physicians to choose the cases for benefitting from the treatment effects prior to or during early treatment ( Zhao et al, 2021b ).…”

POLD1 as a Prognostic Biomarker Correlated with Cell Proliferation and Immune Infiltration in Clear Cell Renal Cell Carcinoma

“…Previous studies have shown that POLD1 is associated with the progression of various cancers. For example, the upregulation of POLD1 in breast and liver cancer is correlated with higher tumor mutation burden and poor prognosis [ 10 , 11 , 12 ]. In addition, the proofreading defect caused by inactivating mutations in the POLD1 proofreading (exonuclease) domain leads to a significant increase in somatic mutation load and cancer risk [ 13 , 14 , 15 ].…”