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

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....

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Autores principales:	Shuai Zhao, Cuicui Wei, Haijia Tang, Han Ding, Bing Han, Shuxian Chen, Xiaoling Song, Qiang Gu, Yichi Zhang, Wangrui Liu, Jian Wang
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	POLD1 hepatocellular carcinoma prognosis immune microenvironment biomarker Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/00386c90fff0454f8beb646c7174ef8d
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spelling	oai:doaj.org-article:00386c90fff0454f8beb646c7174ef8d2021-11-11T11:31:20ZElevated DNA Polymerase Delta 1 Expression Correlates With Tumor Progression and Immunosuppressive Tumor Microenvironment in Hepatocellular Carcinoma2234-943X10.3389/fonc.2021.736363https://doaj.org/article/00386c90fff0454f8beb646c7174ef8d2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.736363/fullhttps://doaj.org/toc/2234-943XBackground 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.Shuai ZhaoCuicui WeiHaijia TangHan DingBing HanShuxian ChenXiaoling SongQiang GuYichi ZhangWangrui LiuWangrui LiuJian WangFrontiers Media S.A.articlePOLD1hepatocellular carcinomaprognosisimmune microenvironmentbiomarkerNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	POLD1 hepatocellular carcinoma prognosis immune microenvironment biomarker Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	POLD1 hepatocellular carcinoma prognosis immune microenvironment biomarker Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Shuai Zhao Cuicui Wei Haijia Tang Han Ding Bing Han Shuxian Chen Xiaoling Song Qiang Gu Yichi Zhang Wangrui Liu Wangrui Liu Jian Wang Elevated DNA Polymerase Delta 1 Expression Correlates With Tumor Progression and Immunosuppressive Tumor Microenvironment in Hepatocellular Carcinoma
description	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.
format	article
author	Shuai Zhao Cuicui Wei Haijia Tang Han Ding Bing Han Shuxian Chen Xiaoling Song Qiang Gu Yichi Zhang Wangrui Liu Wangrui Liu Jian Wang
author_facet	Shuai Zhao Cuicui Wei Haijia Tang Han Ding Bing Han Shuxian Chen Xiaoling Song Qiang Gu Yichi Zhang Wangrui Liu Wangrui Liu Jian Wang
author_sort	Shuai Zhao
title	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_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_sort	elevated dna polymerase delta 1 expression correlates with tumor progression and immunosuppressive tumor microenvironment in hepatocellular carcinoma
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/00386c90fff0454f8beb646c7174ef8d
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Elevated DNA Polymerase Delta 1 Expression Correlates With Tumor Progression and Immunosuppressive Tumor Microenvironment in Hepatocellular Carcinoma

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