PLA2G7 promotes immune evasion of bladder cancer through the JAK-STAT-PDL1 axis
Abstract Targeting immune checkpoints such as Programmed death ligand-1 (PD-L1) and Programmed cell death 1 (PD-1) has been approved for treating bladder cancer and shows promising clinical benefits. However, the relatively low response rate highlights the need to seek an alternative strategy to tra...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-04-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07593-1 |
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| author | Ding Peng Wuping Yang Tianyu Tang Anbang He Xin Xu Taile Jing Dan Xia |
| author_facet | Ding Peng Wuping Yang Tianyu Tang Anbang He Xin Xu Taile Jing Dan Xia |
| author_sort | Ding Peng |
| collection | DOAJ |
| description | Abstract Targeting immune checkpoints such as Programmed death ligand-1 (PD-L1) and Programmed cell death 1 (PD-1) has been approved for treating bladder cancer and shows promising clinical benefits. However, the relatively low response rate highlights the need to seek an alternative strategy to traditional PD-1/PD-L1 targeting immunotherapy. In this study, we found that PLA2G7 is significantly elevated in bladder cancer and correlates with worse prognosis. In vitro experiments demonstrated that knockdown of PLA2G7 does not significantly affect the proliferation, migration, and invasion of bladder cancer cells. Flow cytometry detection, as well as protein and RNA detection, showed that knockdown of PLA2G7 significantly inhibits PD-L1 expression and suppresses the growth of transplanted tumors by promoting CD8 + T-cell infiltration. Further experiments showed that PLA2G7 regulates the JAK-STAT pathway to promote PD-L1 expression by upregulating the phosphorylation of STAT1 and STAT3. Meanwhile, results from syngeneic mouse models indicated that PLA2G7 suppression and anti-CTLA4 therapy have synergistic effects on tumor burden and mouse survival. In addition, we found that ETS1 promotes PLA2G7 overexpression in bladder cancer cells. In summary, our findings provide a novel immunotherapeutic strategy against bladder cancer through targeting the ETS1-PLA2G7-STAT1/STAT3-PD-L1 axis. |
| format | Article |
| id | doaj-art-a26083b37e1640f2813d838cfbda4f8f |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-a26083b37e1640f2813d838cfbda4f8f2025-08-20T03:04:53ZengNature Publishing GroupCell Death and Disease2041-48892025-04-0116111110.1038/s41419-025-07593-1PLA2G7 promotes immune evasion of bladder cancer through the JAK-STAT-PDL1 axisDing Peng0Wuping Yang1Tianyu Tang2Anbang He3Xin Xu4Taile Jing5Dan Xia6Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang UniversityAbstract Targeting immune checkpoints such as Programmed death ligand-1 (PD-L1) and Programmed cell death 1 (PD-1) has been approved for treating bladder cancer and shows promising clinical benefits. However, the relatively low response rate highlights the need to seek an alternative strategy to traditional PD-1/PD-L1 targeting immunotherapy. In this study, we found that PLA2G7 is significantly elevated in bladder cancer and correlates with worse prognosis. In vitro experiments demonstrated that knockdown of PLA2G7 does not significantly affect the proliferation, migration, and invasion of bladder cancer cells. Flow cytometry detection, as well as protein and RNA detection, showed that knockdown of PLA2G7 significantly inhibits PD-L1 expression and suppresses the growth of transplanted tumors by promoting CD8 + T-cell infiltration. Further experiments showed that PLA2G7 regulates the JAK-STAT pathway to promote PD-L1 expression by upregulating the phosphorylation of STAT1 and STAT3. Meanwhile, results from syngeneic mouse models indicated that PLA2G7 suppression and anti-CTLA4 therapy have synergistic effects on tumor burden and mouse survival. In addition, we found that ETS1 promotes PLA2G7 overexpression in bladder cancer cells. In summary, our findings provide a novel immunotherapeutic strategy against bladder cancer through targeting the ETS1-PLA2G7-STAT1/STAT3-PD-L1 axis.https://doi.org/10.1038/s41419-025-07593-1 |
| spellingShingle | Ding Peng Wuping Yang Tianyu Tang Anbang He Xin Xu Taile Jing Dan Xia PLA2G7 promotes immune evasion of bladder cancer through the JAK-STAT-PDL1 axis Cell Death and Disease |
| title | PLA2G7 promotes immune evasion of bladder cancer through the JAK-STAT-PDL1 axis |
| title_full | PLA2G7 promotes immune evasion of bladder cancer through the JAK-STAT-PDL1 axis |
| title_fullStr | PLA2G7 promotes immune evasion of bladder cancer through the JAK-STAT-PDL1 axis |
| title_full_unstemmed | PLA2G7 promotes immune evasion of bladder cancer through the JAK-STAT-PDL1 axis |
| title_short | PLA2G7 promotes immune evasion of bladder cancer through the JAK-STAT-PDL1 axis |
| title_sort | pla2g7 promotes immune evasion of bladder cancer through the jak stat pdl1 axis |
| url | https://doi.org/10.1038/s41419-025-07593-1 |
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