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POLD1 as a Prognostic Biomarker Correlated with Cell Proliferation and Immune Infiltration in Clear Cell Renal Cell Carcinoma
DNA polymerase delta 1 catalytic subunit (POLD1) plays a vital role in genomic copy with high fidelity and DNA damage repair processes. However, the prognostic value of POLD1 and its relationship with tumor immunity in clear cell renal cell carcinoma (ccRCC) remains to be further explored. Transcrip...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10095303/ https://www.ncbi.nlm.nih.gov/pubmed/37047824 http://dx.doi.org/10.3390/ijms24076849 |
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author | Tian, Junjie Cheng, Cheng Gao, Jianguo Fu, Guanghou Xu, Zhijie Chen, Xiaoyi Wu, Yunfei Jin, Baiye |
author_facet | Tian, Junjie Cheng, Cheng Gao, Jianguo Fu, Guanghou Xu, Zhijie Chen, Xiaoyi Wu, Yunfei Jin, Baiye |
author_sort | Tian, Junjie |
collection | PubMed |
description | DNA polymerase delta 1 catalytic subunit (POLD1) plays a vital role in genomic copy with high fidelity and DNA damage repair processes. However, the prognostic value of POLD1 and its relationship with tumor immunity in clear cell renal cell carcinoma (ccRCC) remains to be further explored. Transcriptional data sets and clinical information were obtained from the TCGA, ICGC, and GEO databases. Differentially expressed genes (DEGs) were derived from the comparison between the low and high POLD1 expression groups in the TCGA–KIRC cohort. KEGG and gene ontology (GO) analyses were performed for those DEGs to explore the potential influence of POLD1 on the biological behaviors of ccRCC. The prognostic clinical value and mutational characteristics of patients were described and analyzed according to the POLD1 expression levels. TIMER and TISIDB databases were utilized to comprehensively investigate the potential relevance between the POLD1 levels and the status of the immune cells, as well as the tumor infiltration of immune cells. In addition, RT-qPCR, Western blot, immunohistochemistry and several functional and animal experiments were performed for clinical, in vitro and in vivo validation. POLD1 was highly expressed in a variety of tumors including ccRCC, and further verified in a validation cohort of 60 ccRCC samples and in vitro cell line experiments. POLD1 expression levels in the ccRCC samples were associated with various clinical characteristics including pathologic tumor stage and histologic grade. ccRCC patients with high POLD1 expression have poor clinical outcomes and exhibit a higher rate of somatic mutations than those with low POLD1 expression. Cox regression analysis also showed that POLD1 could act as a potential independent prognostic biomarker. The DEGs associated with POLD1 were significantly enriched in the immunity-related pathways. Moreover, further immune infiltration analysis indicated that high POLD1 expression was associated with high NK CD56bright cells, Treg cells, and myeloid-derived suppressor cells’ (MDSCs) infiltration scores, as well as their marker gene sets of immune cell status. Meanwhile, POLD1 exhibited resistance to various drugs when highly expressed. Finally, the knockdown of POLD1 inhibited the proliferation and migration, and promoted the apoptosis of ccRCC cells in vitro and in vivo, as well as influenced the activation of oncogenic signaling. Our current study demonstrated that POLD1 is a potential prognostic biomarker for ccRCC patients. It might create a tumor immunosuppressive microenvironment and inhibit the susceptibility to ferroptosis leading to a poor prognosis. |
format | Online Article Text |
id | pubmed-10095303 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-100953032023-04-13 POLD1 as a Prognostic Biomarker Correlated with Cell Proliferation and Immune Infiltration in Clear Cell Renal Cell Carcinoma Tian, Junjie Cheng, Cheng Gao, Jianguo Fu, Guanghou Xu, Zhijie Chen, Xiaoyi Wu, Yunfei Jin, Baiye Int J Mol Sci Article DNA polymerase delta 1 catalytic subunit (POLD1) plays a vital role in genomic copy with high fidelity and DNA damage repair processes. However, the prognostic value of POLD1 and its relationship with tumor immunity in clear cell renal cell carcinoma (ccRCC) remains to be further explored. Transcriptional data sets and clinical information were obtained from the TCGA, ICGC, and GEO databases. Differentially expressed genes (DEGs) were derived from the comparison between the low and high POLD1 expression groups in the TCGA–KIRC cohort. KEGG and gene ontology (GO) analyses were performed for those DEGs to explore the potential influence of POLD1 on the biological behaviors of ccRCC. The prognostic clinical value and mutational characteristics of patients were described and analyzed according to the POLD1 expression levels. TIMER and TISIDB databases were utilized to comprehensively investigate the potential relevance between the POLD1 levels and the status of the immune cells, as well as the tumor infiltration of immune cells. In addition, RT-qPCR, Western blot, immunohistochemistry and several functional and animal experiments were performed for clinical, in vitro and in vivo validation. POLD1 was highly expressed in a variety of tumors including ccRCC, and further verified in a validation cohort of 60 ccRCC samples and in vitro cell line experiments. POLD1 expression levels in the ccRCC samples were associated with various clinical characteristics including pathologic tumor stage and histologic grade. ccRCC patients with high POLD1 expression have poor clinical outcomes and exhibit a higher rate of somatic mutations than those with low POLD1 expression. Cox regression analysis also showed that POLD1 could act as a potential independent prognostic biomarker. The DEGs associated with POLD1 were significantly enriched in the immunity-related pathways. Moreover, further immune infiltration analysis indicated that high POLD1 expression was associated with high NK CD56bright cells, Treg cells, and myeloid-derived suppressor cells’ (MDSCs) infiltration scores, as well as their marker gene sets of immune cell status. Meanwhile, POLD1 exhibited resistance to various drugs when highly expressed. Finally, the knockdown of POLD1 inhibited the proliferation and migration, and promoted the apoptosis of ccRCC cells in vitro and in vivo, as well as influenced the activation of oncogenic signaling. Our current study demonstrated that POLD1 is a potential prognostic biomarker for ccRCC patients. It might create a tumor immunosuppressive microenvironment and inhibit the susceptibility to ferroptosis leading to a poor prognosis. MDPI 2023-04-06 /pmc/articles/PMC10095303/ /pubmed/37047824 http://dx.doi.org/10.3390/ijms24076849 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Tian, Junjie Cheng, Cheng Gao, Jianguo Fu, Guanghou Xu, Zhijie Chen, Xiaoyi Wu, Yunfei Jin, Baiye POLD1 as a Prognostic Biomarker Correlated with Cell Proliferation and Immune Infiltration in Clear Cell Renal Cell Carcinoma |
title | POLD1 as a Prognostic Biomarker Correlated with Cell Proliferation and Immune Infiltration in Clear Cell Renal Cell Carcinoma |
title_full | POLD1 as a Prognostic Biomarker Correlated with Cell Proliferation and Immune Infiltration in Clear Cell Renal Cell Carcinoma |
title_fullStr | POLD1 as a Prognostic Biomarker Correlated with Cell Proliferation and Immune Infiltration in Clear Cell Renal Cell Carcinoma |
title_full_unstemmed | POLD1 as a Prognostic Biomarker Correlated with Cell Proliferation and Immune Infiltration in Clear Cell Renal Cell Carcinoma |
title_short | POLD1 as a Prognostic Biomarker Correlated with Cell Proliferation and Immune Infiltration in Clear Cell Renal Cell Carcinoma |
title_sort | pold1 as a prognostic biomarker correlated with cell proliferation and immune infiltration in clear cell renal cell carcinoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10095303/ https://www.ncbi.nlm.nih.gov/pubmed/37047824 http://dx.doi.org/10.3390/ijms24076849 |
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