CircNF1 modulates the progression and immune evasion of esophageal squamous cell carcinoma through dual regulation of PD-L1
Abstract Background Tumor immune escape is a pivotal gateway for esophageal squamous cell carcinoma (ESCC) development. Immune checkpoint-blocking therapies, represented by programmed cell death receptor-1/ligand 1 (PD-1/PD-L1) inhibitors, have achieved remarkable breakthroughs in ESCC treatment. Ho...
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| Language: | English |
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BMC
2025-03-01
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| Series: | Cellular & Molecular Biology Letters |
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| Online Access: | https://doi.org/10.1186/s11658-025-00712-y |
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| author | Chang Wang Chenxi Ju Dan Du Peiyu Zhu Jie Yin Jinlin Jia Xue Wang Xinyu Xu Li Zhao Junhu Wan Ting Sun Lijun Yang Hongle Li Fucheng He Mingxia Zhou Jing He |
| author_facet | Chang Wang Chenxi Ju Dan Du Peiyu Zhu Jie Yin Jinlin Jia Xue Wang Xinyu Xu Li Zhao Junhu Wan Ting Sun Lijun Yang Hongle Li Fucheng He Mingxia Zhou Jing He |
| author_sort | Chang Wang |
| collection | DOAJ |
| description | Abstract Background Tumor immune escape is a pivotal gateway for esophageal squamous cell carcinoma (ESCC) development. Immune checkpoint-blocking therapies, represented by programmed cell death receptor-1/ligand 1 (PD-1/PD-L1) inhibitors, have achieved remarkable breakthroughs in ESCC treatment. However, not all patients with ESCC receive satisfactory clinical benefit. Therefore, identifying novel biomarkers for predicting the efficacy of immunotherapy in ESCC is of great importance. Methods CircNF1 was screened from the circRNAs microarray, and its expression was measured by droplet digital polymerase chain reaction (ddPCR) and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assays in ESCC tissues and serum. Functional experiments were conducted to demonstrate the role of circNF1 in ESCC proliferation, metastasis, and tumor evasion. High-throughput RNA sequencing, chromatin immunoprecipitation (ChIP), co-immunoprecipitation (co-IP), and chromatin isolation by RNA purification-mass spectrometry (ChIRP-MS) were performed to clarify the underlying mechanisms of circNF1-mediated tumor progression. Results The upregulation of circNF1 was closely associated with the response of anti-PD-L1 immunotherapy. Functionally, circNF1 promoted ESCC cell malignant phenotypes and regulated CD8+ T-cell-mediated antitumor immunity. Mechanistically, circNF1 drove the IL-6-induced oncogenic activation of the JAK–STAT3 pathway, which stimulated p-STAT3 binding of the promoter regions of PD-L1. Furthermore, circNF1 physically interacted with annexin A1 (ANXA1), blocking the ANXA1 deubiquitination induced by ubiquitin-specific protease 7 (USP7), resulting in increased interaction between USP7 and PD-L1 and augmented PD-L1 stability. Conclusions Our findings provide novel insights into the specific regulatory mechanism of PD-L1 in ESCC cells, which offer a new strategy for synergizing with anti-PD-L1 therapy. |
| format | Article |
| id | doaj-art-c23672c38e4b40e2ab3a3f89a354c12b |
| institution | OA Journals |
| issn | 1689-1392 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Cellular & Molecular Biology Letters |
| spelling | doaj-art-c23672c38e4b40e2ab3a3f89a354c12b2025-08-20T02:10:17ZengBMCCellular & Molecular Biology Letters1689-13922025-03-0130112710.1186/s11658-025-00712-yCircNF1 modulates the progression and immune evasion of esophageal squamous cell carcinoma through dual regulation of PD-L1Chang Wang0Chenxi Ju1Dan Du2Peiyu Zhu3Jie Yin4Jinlin Jia5Xue Wang6Xinyu Xu7Li Zhao8Junhu Wan9Ting Sun10Lijun Yang11Hongle Li12Fucheng He13Mingxia Zhou14Jing He15Department of Medical Laboratory, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Medical Laboratory, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Medical Laboratory, The First Affiliated Hospital of Zhengzhou UniversityKey Laboratory of Carcinogenesis and Translational Research, Center of Gastrointestinal Cancer, Peking University Cancer Hospital and InstituteDepartment of Oncology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Medical Laboratory, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Medical Laboratory, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Medical Laboratory, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Research and Development, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Medical Laboratory, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Medical Laboratory, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Medical Laboratory, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou UniversityDepartment of Medical Laboratory, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Gastroenterology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Breast Surgery, The First Affiliated Hospital of Zhengzhou UniversityAbstract Background Tumor immune escape is a pivotal gateway for esophageal squamous cell carcinoma (ESCC) development. Immune checkpoint-blocking therapies, represented by programmed cell death receptor-1/ligand 1 (PD-1/PD-L1) inhibitors, have achieved remarkable breakthroughs in ESCC treatment. However, not all patients with ESCC receive satisfactory clinical benefit. Therefore, identifying novel biomarkers for predicting the efficacy of immunotherapy in ESCC is of great importance. Methods CircNF1 was screened from the circRNAs microarray, and its expression was measured by droplet digital polymerase chain reaction (ddPCR) and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assays in ESCC tissues and serum. Functional experiments were conducted to demonstrate the role of circNF1 in ESCC proliferation, metastasis, and tumor evasion. High-throughput RNA sequencing, chromatin immunoprecipitation (ChIP), co-immunoprecipitation (co-IP), and chromatin isolation by RNA purification-mass spectrometry (ChIRP-MS) were performed to clarify the underlying mechanisms of circNF1-mediated tumor progression. Results The upregulation of circNF1 was closely associated with the response of anti-PD-L1 immunotherapy. Functionally, circNF1 promoted ESCC cell malignant phenotypes and regulated CD8+ T-cell-mediated antitumor immunity. Mechanistically, circNF1 drove the IL-6-induced oncogenic activation of the JAK–STAT3 pathway, which stimulated p-STAT3 binding of the promoter regions of PD-L1. Furthermore, circNF1 physically interacted with annexin A1 (ANXA1), blocking the ANXA1 deubiquitination induced by ubiquitin-specific protease 7 (USP7), resulting in increased interaction between USP7 and PD-L1 and augmented PD-L1 stability. Conclusions Our findings provide novel insights into the specific regulatory mechanism of PD-L1 in ESCC cells, which offer a new strategy for synergizing with anti-PD-L1 therapy.https://doi.org/10.1186/s11658-025-00712-yEsophageal squamous cell carcinoma (ESCC)circRNAsSTAT3ANXA1PD-L1 |
| spellingShingle | Chang Wang Chenxi Ju Dan Du Peiyu Zhu Jie Yin Jinlin Jia Xue Wang Xinyu Xu Li Zhao Junhu Wan Ting Sun Lijun Yang Hongle Li Fucheng He Mingxia Zhou Jing He CircNF1 modulates the progression and immune evasion of esophageal squamous cell carcinoma through dual regulation of PD-L1 Cellular & Molecular Biology Letters Esophageal squamous cell carcinoma (ESCC) circRNAs STAT3 ANXA1 PD-L1 |
| title | CircNF1 modulates the progression and immune evasion of esophageal squamous cell carcinoma through dual regulation of PD-L1 |
| title_full | CircNF1 modulates the progression and immune evasion of esophageal squamous cell carcinoma through dual regulation of PD-L1 |
| title_fullStr | CircNF1 modulates the progression and immune evasion of esophageal squamous cell carcinoma through dual regulation of PD-L1 |
| title_full_unstemmed | CircNF1 modulates the progression and immune evasion of esophageal squamous cell carcinoma through dual regulation of PD-L1 |
| title_short | CircNF1 modulates the progression and immune evasion of esophageal squamous cell carcinoma through dual regulation of PD-L1 |
| title_sort | circnf1 modulates the progression and immune evasion of esophageal squamous cell carcinoma through dual regulation of pd l1 |
| topic | Esophageal squamous cell carcinoma (ESCC) circRNAs STAT3 ANXA1 PD-L1 |
| url | https://doi.org/10.1186/s11658-025-00712-y |
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