Cargando…
Elevated DNA Polymerase Delta 1 Expression Correlates With Tumor Progression and Immunosuppressive Tumor Microenvironment in Hepatocellular Carcinoma
BACKGROUND AND OBJECTIVE: Hepatocellular 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) pathwa...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8632622/ https://www.ncbi.nlm.nih.gov/pubmed/34868924 http://dx.doi.org/10.3389/fonc.2021.736363 |
_version_ | 1784607784504918016 |
---|---|
author | Zhao, Shuai Wei, Cuicui Tang, Haijia Ding, Han Han, Bing Chen, Shuxian Song, Xiaoling Gu, Qiang Zhang, Yichi Liu, Wangrui Wang, Jian |
author_facet | Zhao, Shuai Wei, Cuicui Tang, Haijia Ding, Han Han, Bing Chen, Shuxian Song, Xiaoling Gu, Qiang Zhang, Yichi Liu, Wangrui Wang, Jian |
author_sort | Zhao, Shuai |
collection | PubMed |
description | BACKGROUND AND OBJECTIVE: Hepatocellular 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. METHODS: Data 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. RESULTS: The 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. CONCLUSION: We 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. |
format | Online Article Text |
id | pubmed-8632622 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-86326222021-12-02 Elevated DNA Polymerase Delta 1 Expression Correlates With Tumor Progression and Immunosuppressive Tumor Microenvironment in Hepatocellular Carcinoma Zhao, Shuai Wei, Cuicui Tang, Haijia Ding, Han Han, Bing Chen, Shuxian Song, Xiaoling Gu, Qiang Zhang, Yichi Liu, Wangrui Wang, Jian Front Oncol Oncology BACKGROUND AND OBJECTIVE: Hepatocellular 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. METHODS: Data 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. RESULTS: The 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. CONCLUSION: We 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. Frontiers Media S.A. 2021-11-11 /pmc/articles/PMC8632622/ /pubmed/34868924 http://dx.doi.org/10.3389/fonc.2021.736363 Text en Copyright © 2021 Zhao, Wei, Tang, Ding, Han, Chen, Song, Gu, Zhang, Liu and Wang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Zhao, Shuai Wei, Cuicui Tang, Haijia Ding, Han Han, Bing Chen, Shuxian Song, Xiaoling Gu, Qiang Zhang, Yichi Liu, Wangrui Wang, Jian Elevated DNA Polymerase Delta 1 Expression Correlates With Tumor Progression and Immunosuppressive Tumor Microenvironment in Hepatocellular Carcinoma |
title | Elevated DNA Polymerase Delta 1 Expression Correlates With Tumor Progression and Immunosuppressive Tumor Microenvironment in Hepatocellular Carcinoma |
title_full | Elevated DNA Polymerase Delta 1 Expression Correlates With Tumor Progression and Immunosuppressive Tumor Microenvironment in Hepatocellular Carcinoma |
title_fullStr | Elevated DNA Polymerase Delta 1 Expression Correlates With Tumor Progression and Immunosuppressive Tumor Microenvironment in Hepatocellular Carcinoma |
title_full_unstemmed | Elevated DNA Polymerase Delta 1 Expression Correlates With Tumor Progression and Immunosuppressive Tumor Microenvironment in Hepatocellular Carcinoma |
title_short | Elevated DNA Polymerase Delta 1 Expression Correlates With Tumor Progression and Immunosuppressive Tumor Microenvironment in Hepatocellular Carcinoma |
title_sort | elevated dna polymerase delta 1 expression correlates with tumor progression and immunosuppressive tumor microenvironment in hepatocellular carcinoma |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8632622/ https://www.ncbi.nlm.nih.gov/pubmed/34868924 http://dx.doi.org/10.3389/fonc.2021.736363 |
work_keys_str_mv | AT zhaoshuai elevateddnapolymerasedelta1expressioncorrelateswithtumorprogressionandimmunosuppressivetumormicroenvironmentinhepatocellularcarcinoma AT weicuicui elevateddnapolymerasedelta1expressioncorrelateswithtumorprogressionandimmunosuppressivetumormicroenvironmentinhepatocellularcarcinoma AT tanghaijia elevateddnapolymerasedelta1expressioncorrelateswithtumorprogressionandimmunosuppressivetumormicroenvironmentinhepatocellularcarcinoma AT dinghan elevateddnapolymerasedelta1expressioncorrelateswithtumorprogressionandimmunosuppressivetumormicroenvironmentinhepatocellularcarcinoma AT hanbing elevateddnapolymerasedelta1expressioncorrelateswithtumorprogressionandimmunosuppressivetumormicroenvironmentinhepatocellularcarcinoma AT chenshuxian elevateddnapolymerasedelta1expressioncorrelateswithtumorprogressionandimmunosuppressivetumormicroenvironmentinhepatocellularcarcinoma AT songxiaoling elevateddnapolymerasedelta1expressioncorrelateswithtumorprogressionandimmunosuppressivetumormicroenvironmentinhepatocellularcarcinoma AT guqiang elevateddnapolymerasedelta1expressioncorrelateswithtumorprogressionandimmunosuppressivetumormicroenvironmentinhepatocellularcarcinoma AT zhangyichi elevateddnapolymerasedelta1expressioncorrelateswithtumorprogressionandimmunosuppressivetumormicroenvironmentinhepatocellularcarcinoma AT liuwangrui elevateddnapolymerasedelta1expressioncorrelateswithtumorprogressionandimmunosuppressivetumormicroenvironmentinhepatocellularcarcinoma AT wangjian elevateddnapolymerasedelta1expressioncorrelateswithtumorprogressionandimmunosuppressivetumormicroenvironmentinhepatocellularcarcinoma |