PCSK9 promotes progression of anaplastic thyroid cancer through E-cadherin endocytosis
Abstract Although anaplastic thyroid cancer (ATC) constitutes only 1–2% of all thyroid malignancies, it is associated with an exceptionally high mortality rate, accounting for 14–39% of thyroid cancer-related deaths. In this study, we identified the critical role of Proprotein Convertase Subtilisin/...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-05-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07690-1 |
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| author | Yu Zhang Wei Su Xiaoyu Ji Zhou Yang Qing Guan Yuanxin Pang Linkun Zhong Yu Wang Jun Xiang |
| author_facet | Yu Zhang Wei Su Xiaoyu Ji Zhou Yang Qing Guan Yuanxin Pang Linkun Zhong Yu Wang Jun Xiang |
| author_sort | Yu Zhang |
| collection | DOAJ |
| description | Abstract Although anaplastic thyroid cancer (ATC) constitutes only 1–2% of all thyroid malignancies, it is associated with an exceptionally high mortality rate, accounting for 14–39% of thyroid cancer-related deaths. In this study, we identified the critical role of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in ATC progression. Proteomic analysis revealed E-cadherin as a key mediator of PCSK9-driven malignancy in ATC. Mechanistically, PCSK9 promotes the degradation of E-cadherin through the lysosomal pathway. Furthermore, the loss of the p53 function, particularly the R248Q mutation, de-repressed PCSK9 expression at the transcriptional level. Notably, the PCSK9 inhibitor PF-846 considerably suppressed ATC proliferation and metastasis in both in vitro and in vivo models. In conclusion, PCSK9 enhances ATC malignancy by regulating E-cadherin degradation via the lysosomal pathway, underscoring its potential as a promising therapeutic target. |
| format | Article |
| id | doaj-art-534b6346b7364ee6a87a455f8b931ec2 |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-534b6346b7364ee6a87a455f8b931ec22025-08-20T03:09:20ZengNature Publishing GroupCell Death and Disease2041-48892025-05-0116111410.1038/s41419-025-07690-1PCSK9 promotes progression of anaplastic thyroid cancer through E-cadherin endocytosisYu Zhang0Wei Su1Xiaoyu Ji2Zhou Yang3Qing Guan4Yuanxin Pang5Linkun Zhong6Yu Wang7Jun Xiang8Department of Head and Neck Surgery, Fudan University Shanghai Cancer CenterDepartment of Oncology, Shanghai Medical College, Fudan UniversityDepartment of Oncology, Huashan Hospital Fudan UniversityDepartment of Head and Neck Surgery, Fudan University Shanghai Cancer CenterDepartment of Head and Neck Surgery, Fudan University Shanghai Cancer CenterDepartment of Endocrinology, Suzhou Ninth People’s Hospital Affiliated to Soochow UniversityDepartment of General Surgery, Zhongshan City People’s HospitalDepartment of Head and Neck Surgery, Fudan University Shanghai Cancer CenterDepartment of Head and Neck Surgery, Fudan University Shanghai Cancer CenterAbstract Although anaplastic thyroid cancer (ATC) constitutes only 1–2% of all thyroid malignancies, it is associated with an exceptionally high mortality rate, accounting for 14–39% of thyroid cancer-related deaths. In this study, we identified the critical role of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in ATC progression. Proteomic analysis revealed E-cadherin as a key mediator of PCSK9-driven malignancy in ATC. Mechanistically, PCSK9 promotes the degradation of E-cadherin through the lysosomal pathway. Furthermore, the loss of the p53 function, particularly the R248Q mutation, de-repressed PCSK9 expression at the transcriptional level. Notably, the PCSK9 inhibitor PF-846 considerably suppressed ATC proliferation and metastasis in both in vitro and in vivo models. In conclusion, PCSK9 enhances ATC malignancy by regulating E-cadherin degradation via the lysosomal pathway, underscoring its potential as a promising therapeutic target.https://doi.org/10.1038/s41419-025-07690-1 |
| spellingShingle | Yu Zhang Wei Su Xiaoyu Ji Zhou Yang Qing Guan Yuanxin Pang Linkun Zhong Yu Wang Jun Xiang PCSK9 promotes progression of anaplastic thyroid cancer through E-cadherin endocytosis Cell Death and Disease |
| title | PCSK9 promotes progression of anaplastic thyroid cancer through E-cadherin endocytosis |
| title_full | PCSK9 promotes progression of anaplastic thyroid cancer through E-cadherin endocytosis |
| title_fullStr | PCSK9 promotes progression of anaplastic thyroid cancer through E-cadherin endocytosis |
| title_full_unstemmed | PCSK9 promotes progression of anaplastic thyroid cancer through E-cadherin endocytosis |
| title_short | PCSK9 promotes progression of anaplastic thyroid cancer through E-cadherin endocytosis |
| title_sort | pcsk9 promotes progression of anaplastic thyroid cancer through e cadherin endocytosis |
| url | https://doi.org/10.1038/s41419-025-07690-1 |
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