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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MDPI AG
2023-08-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/14/8/1620 |
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| author | Zike Chen Hui Pi Wen Zheng Xiaohong Guo Conglin Shi Zhiyang Wang Jie Zhang Xuanhao Qu Lehan Liu Haoliang Shen Yang Lu Miaomiao Chen Weibing Zhang Rong Sun Yihui Fan |
| author_facet | Zike Chen Hui Pi Wen Zheng Xiaohong Guo Conglin Shi Zhiyang Wang Jie Zhang Xuanhao Qu Lehan Liu Haoliang Shen Yang Lu Miaomiao Chen Weibing Zhang Rong Sun Yihui Fan |
| author_sort | Zike Chen |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T23:54:03Z |
| format | Article |
| id | doaj.art-21889718c94d4bef827993a8c01948a1 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-10T23:54:03Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-21889718c94d4bef827993a8c01948a12023-11-19T01:16:02ZengMDPI AGGenes2073-44252023-08-01148162010.3390/genes14081620The 3′ Non-Coding Sequence Negatively Regulates PD-L1 Expression, and Its Regulators Are Systematically Identified in Pan-CancerZike Chen0Hui Pi1Wen Zheng2Xiaohong Guo3Conglin Shi4Zhiyang Wang5Jie Zhang6Xuanhao Qu7Lehan Liu8Haoliang Shen9Yang Lu10Miaomiao Chen11Weibing Zhang12Rong Sun13Yihui Fan14Laboratory of Medical Science, School of Medicine, Nantong University, Nantong 226001, ChinaDepartment of Pathophysiology, School of Medicine, Nantong University, Nantong 226001, ChinaDepartment of Pathogenic Biology, School of Medicine, Nantong University, Nantong 226001, ChinaDepartment of Pathogenic Biology, School of Medicine, Nantong University, Nantong 226001, ChinaDepartment of Pathogenic Biology, School of Medicine, Nantong University, Nantong 226001, ChinaLaboratory of Medical Science, School of Medicine, Nantong University, Nantong 226001, ChinaLaboratory of Medical Science, School of Medicine, Nantong University, Nantong 226001, ChinaLaboratory of Medical Science, School of Medicine, Nantong University, Nantong 226001, ChinaLaboratory of Medical Science, School of Medicine, Nantong University, Nantong 226001, ChinaThe Intensive Care Unit, Affiliated Hospital of Nantong University, Nantong 226001, ChinaThe Intensive Care Unit, Affiliated Hospital of Nantong University, Nantong 226001, ChinaLaboratory of Medical Science, School of Medicine, Nantong University, Nantong 226001, ChinaNantong Center for Disease Control and Prevention, Nantong 226001, ChinaLaboratory of Medical Science, School of Medicine, Nantong University, Nantong 226001, ChinaLaboratory of Medical Science, School of Medicine, Nantong University, Nantong 226001, ChinaThe 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.https://www.mdpi.com/2073-4425/14/8/16203′-untranslated region (3′-UTR)PD-L1RNA-binding proteins (RBPs)miRNAsm6A regulator |
| spellingShingle | Zike Chen Hui Pi Wen Zheng Xiaohong Guo Conglin Shi Zhiyang Wang Jie Zhang Xuanhao Qu Lehan Liu Haoliang Shen Yang Lu Miaomiao Chen Weibing Zhang Rong Sun Yihui Fan The 3′ Non-Coding Sequence Negatively Regulates PD-L1 Expression, and Its Regulators Are Systematically Identified in Pan-Cancer Genes 3′-untranslated region (3′-UTR) PD-L1 RNA-binding proteins (RBPs) miRNAs m6A regulator |
| 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 | 3′-untranslated region (3′-UTR) PD-L1 RNA-binding proteins (RBPs) miRNAs m6A regulator |
| url | https://www.mdpi.com/2073-4425/14/8/1620 |
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