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The 3′ Non-Coding Sequence Negatively Regulates PD-L1 Expression, and Its Regulators Are Systematically Identified in Pan-Cancer

The 3′-untranslated region (3′-UTR) of PD-L1 is significantly longer than the coding sequences (CDSs). However, its role and regulators have been little studied. We deleted whole 3′-UTR region by CRISPR-Cas9. Prognostic analysis was performed using online tools. Immune infiltration analysis was perf...

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Autores principales: Chen, Zike, Pi, Hui, Zheng, Wen, Guo, Xiaohong, Shi, Conglin, Wang, Zhiyang, Zhang, Jie, Qu, Xuanhao, Liu, Lehan, Shen, Haoliang, Lu, Yang, Chen, Miaomiao, Zhang, Weibing, Sun, Rong, Fan, Yihui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10454350/
https://www.ncbi.nlm.nih.gov/pubmed/37628671
http://dx.doi.org/10.3390/genes14081620
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author Chen, Zike
Pi, Hui
Zheng, Wen
Guo, Xiaohong
Shi, Conglin
Wang, Zhiyang
Zhang, Jie
Qu, Xuanhao
Liu, Lehan
Shen, Haoliang
Lu, Yang
Chen, Miaomiao
Zhang, Weibing
Sun, Rong
Fan, Yihui
author_facet Chen, Zike
Pi, Hui
Zheng, Wen
Guo, Xiaohong
Shi, Conglin
Wang, Zhiyang
Zhang, Jie
Qu, Xuanhao
Liu, Lehan
Shen, Haoliang
Lu, Yang
Chen, Miaomiao
Zhang, Weibing
Sun, Rong
Fan, Yihui
author_sort Chen, Zike
collection PubMed
description The 3′-untranslated region (3′-UTR) of PD-L1 is significantly longer than the coding sequences (CDSs). However, its role and regulators have been little studied. We deleted whole 3′-UTR region by CRISPR-Cas9. Prognostic analysis was performed using online tools. Immune infiltration analysis was performed using the Timer and Xcell packages. Immunotherapy response prediction and Cox regression was performed using the R software. MicroRNA network analysis was conducted by the Cytoscape software. The level of PD-L1 was significantly and dramatically up-regulated in cells after deleting the 3′-UTR. Additionally, we discovered a panel of 43 RNA-binding proteins (RBPs) whose expression correlates with PD-L1 in the majority of cancer cell lines and tumor tissues. Among these RBPs, PARP14 is widely associated with immune checkpoints, the tumor microenvironment, and immune-infiltrating cells in various cancer types. We also identified 38 microRNAs whose individual expressions are associated with PD-L1 across different cancers. Notably, miR-3139, miR-4761, and miR-15a-5p showed significant associations with PD-L1 in most cancer types. Furthermore, we revealed 21 m6A regulators that strongly correlate with PD-L1. Importantly, by combining the identified RBP and m6A regulators, we established an immune signature consisting of RBMS1, QKI, ZC3HAV1, and RBM38. This signature can be used to predict the responsiveness of cancer patients to immune checkpoint blockade treatment. We demonstrated the critical role of the 3′-UTR in the regulation of PD-L1 and identified a significant number of potential PD-L1 regulators across various types of cancer. The biomarker signature generated from our findings shows promise in predicting patient prognosis. However, further biological investigation is necessary to explore the potential of these PD-L1 regulators.
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spelling pubmed-104543502023-08-26 The 3′ Non-Coding Sequence Negatively Regulates PD-L1 Expression, and Its Regulators Are Systematically Identified in Pan-Cancer Chen, Zike Pi, Hui Zheng, Wen Guo, Xiaohong Shi, Conglin Wang, Zhiyang Zhang, Jie Qu, Xuanhao Liu, Lehan Shen, Haoliang Lu, Yang Chen, Miaomiao Zhang, Weibing Sun, Rong Fan, Yihui Genes (Basel) Article The 3′-untranslated region (3′-UTR) of PD-L1 is significantly longer than the coding sequences (CDSs). However, its role and regulators have been little studied. We deleted whole 3′-UTR region by CRISPR-Cas9. Prognostic analysis was performed using online tools. Immune infiltration analysis was performed using the Timer and Xcell packages. Immunotherapy response prediction and Cox regression was performed using the R software. MicroRNA network analysis was conducted by the Cytoscape software. The level of PD-L1 was significantly and dramatically up-regulated in cells after deleting the 3′-UTR. Additionally, we discovered a panel of 43 RNA-binding proteins (RBPs) whose expression correlates with PD-L1 in the majority of cancer cell lines and tumor tissues. Among these RBPs, PARP14 is widely associated with immune checkpoints, the tumor microenvironment, and immune-infiltrating cells in various cancer types. We also identified 38 microRNAs whose individual expressions are associated with PD-L1 across different cancers. Notably, miR-3139, miR-4761, and miR-15a-5p showed significant associations with PD-L1 in most cancer types. Furthermore, we revealed 21 m6A regulators that strongly correlate with PD-L1. Importantly, by combining the identified RBP and m6A regulators, we established an immune signature consisting of RBMS1, QKI, ZC3HAV1, and RBM38. This signature can be used to predict the responsiveness of cancer patients to immune checkpoint blockade treatment. We demonstrated the critical role of the 3′-UTR in the regulation of PD-L1 and identified a significant number of potential PD-L1 regulators across various types of cancer. The biomarker signature generated from our findings shows promise in predicting patient prognosis. However, further biological investigation is necessary to explore the potential of these PD-L1 regulators. MDPI 2023-08-13 /pmc/articles/PMC10454350/ /pubmed/37628671 http://dx.doi.org/10.3390/genes14081620 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
Chen, Zike
Pi, Hui
Zheng, Wen
Guo, Xiaohong
Shi, Conglin
Wang, Zhiyang
Zhang, Jie
Qu, Xuanhao
Liu, Lehan
Shen, Haoliang
Lu, Yang
Chen, Miaomiao
Zhang, Weibing
Sun, Rong
Fan, Yihui
The 3′ Non-Coding Sequence Negatively Regulates PD-L1 Expression, and Its Regulators Are Systematically Identified in Pan-Cancer
title The 3′ Non-Coding Sequence Negatively Regulates PD-L1 Expression, and Its Regulators Are Systematically Identified in Pan-Cancer
title_full The 3′ Non-Coding Sequence Negatively Regulates PD-L1 Expression, and Its Regulators Are Systematically Identified in Pan-Cancer
title_fullStr The 3′ Non-Coding Sequence Negatively Regulates PD-L1 Expression, and Its Regulators Are Systematically Identified in Pan-Cancer
title_full_unstemmed The 3′ Non-Coding Sequence Negatively Regulates PD-L1 Expression, and Its Regulators Are Systematically Identified in Pan-Cancer
title_short The 3′ Non-Coding Sequence Negatively Regulates PD-L1 Expression, and Its Regulators Are Systematically Identified in Pan-Cancer
title_sort 3′ non-coding sequence negatively regulates pd-l1 expression, and its regulators are systematically identified in pan-cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10454350/
https://www.ncbi.nlm.nih.gov/pubmed/37628671
http://dx.doi.org/10.3390/genes14081620
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