The feedback loop between miR-222-3p and ZEB1 harnesses metastasis in renal cell carcinoma
Abstract Renal cell carcinoma (RCC) is an aggressive malignancy originating from the renal parenchyma, often leading to high mortality due to local invasion and distant metastasis. MicroRNAs (miRNAs) play essential roles in RCC progression. Through miRNA sequencing, we identified significant upregul...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-03-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02385-0 |
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| author | Fan Wang Liao Li Xiangfu Sun Xianfu Cai Jianjun Wang Huiwen Luo Yaodong Wang Dong Ni Decai Wang |
| author_facet | Fan Wang Liao Li Xiangfu Sun Xianfu Cai Jianjun Wang Huiwen Luo Yaodong Wang Dong Ni Decai Wang |
| author_sort | Fan Wang |
| collection | DOAJ |
| description | Abstract Renal cell carcinoma (RCC) is an aggressive malignancy originating from the renal parenchyma, often leading to high mortality due to local invasion and distant metastasis. MicroRNAs (miRNAs) play essential roles in RCC progression. Through miRNA sequencing, we identified significant upregulation of miR-222-3p in metastatic RCC tissues. Exosomes from highly metastatic RCC cells were found to transfer miR-222-3p to low-metastatic cells, enhancing their migration and invasion. Mechanistically, miR-222-3p directly targets the 3′ untranslated region (3′UTR) of the tumor-suppressor TRPS1, reducing its expression. TRPS1 downregulation releases its inhibitory effect on ZEB1, a key regulator of epithelial-mesenchymal transition (EMT), thereby promoting EMT and metastatic traits. ZEB1 further transactivates miR-222-3p, establishing a positive feedback loop. Additionally, miR-222-3p promotes a pre-metastatic niche by inducing M2 macrophage polarization, facilitating distant metastasis. These findings highlight miR-222-3p as a critical driver of RCC metastasis and suggest its potential as a diagnostic marker and therapeutic target for RCC. |
| format | Article |
| id | doaj-art-ad8fcf01b6584ba9aa0b37c273e28ee6 |
| institution | DOAJ |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-ad8fcf01b6584ba9aa0b37c273e28ee62025-08-20T02:56:09ZengNature Publishing GroupCell Death Discovery2058-77162025-03-0111111410.1038/s41420-025-02385-0The feedback loop between miR-222-3p and ZEB1 harnesses metastasis in renal cell carcinomaFan Wang0Liao Li1Xiangfu Sun2Xianfu Cai3Jianjun Wang4Huiwen Luo5Yaodong Wang6Dong Ni7Decai Wang8Department of Thyroid and Breast Surgery, Xiangyang No. 1 People’s Hospital, Hubei University of MedicineDepartment of Child Healthcare, Xiangyang No. 1 People’s Hospital, Hubei University of MedicineDepartment of Cardiothoracic Surgery, Xiangyang No. 1 People’s Hospital, Hubei University of MedicineDepartment of Renal Transplantation, the First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of ChinaNHC Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of ChinaDepartment of Urology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of ChinaDepartment of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Urology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of ChinaAbstract Renal cell carcinoma (RCC) is an aggressive malignancy originating from the renal parenchyma, often leading to high mortality due to local invasion and distant metastasis. MicroRNAs (miRNAs) play essential roles in RCC progression. Through miRNA sequencing, we identified significant upregulation of miR-222-3p in metastatic RCC tissues. Exosomes from highly metastatic RCC cells were found to transfer miR-222-3p to low-metastatic cells, enhancing their migration and invasion. Mechanistically, miR-222-3p directly targets the 3′ untranslated region (3′UTR) of the tumor-suppressor TRPS1, reducing its expression. TRPS1 downregulation releases its inhibitory effect on ZEB1, a key regulator of epithelial-mesenchymal transition (EMT), thereby promoting EMT and metastatic traits. ZEB1 further transactivates miR-222-3p, establishing a positive feedback loop. Additionally, miR-222-3p promotes a pre-metastatic niche by inducing M2 macrophage polarization, facilitating distant metastasis. These findings highlight miR-222-3p as a critical driver of RCC metastasis and suggest its potential as a diagnostic marker and therapeutic target for RCC.https://doi.org/10.1038/s41420-025-02385-0 |
| spellingShingle | Fan Wang Liao Li Xiangfu Sun Xianfu Cai Jianjun Wang Huiwen Luo Yaodong Wang Dong Ni Decai Wang The feedback loop between miR-222-3p and ZEB1 harnesses metastasis in renal cell carcinoma Cell Death Discovery |
| title | The feedback loop between miR-222-3p and ZEB1 harnesses metastasis in renal cell carcinoma |
| title_full | The feedback loop between miR-222-3p and ZEB1 harnesses metastasis in renal cell carcinoma |
| title_fullStr | The feedback loop between miR-222-3p and ZEB1 harnesses metastasis in renal cell carcinoma |
| title_full_unstemmed | The feedback loop between miR-222-3p and ZEB1 harnesses metastasis in renal cell carcinoma |
| title_short | The feedback loop between miR-222-3p and ZEB1 harnesses metastasis in renal cell carcinoma |
| title_sort | feedback loop between mir 222 3p and zeb1 harnesses metastasis in renal cell carcinoma |
| url | https://doi.org/10.1038/s41420-025-02385-0 |
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