PCSK9 promotes progression of anaplastic thyroid cancer through E-cadherin endocytosis

  • Cell Death Dis. 2025 May 6;16(1):362. doi: 10.1038/s41419-025-07690-1.
Yu Zhang  #  1  2 ,  Wei Su  #  2  3 ,  Xiaoyu Ji  #  4 ,  Zhou Yang  1  2 ,  Qing Guan  1  2 ,  Yuanxin Pang  5 ,  Linkun Zhong  6 ,  Yu Wang  7  8 ,  Jun Xiang  9  10
Affiliations
  • 1. Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
  • 2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • 3. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 4. Department of Oncology, Huashan Hospital Fudan University, Shanghai, China.
  • 5. Department of Endocrinology, Suzhou Ninth People's Hospital Affiliated to Soochow University, Suzhou, China. [email protected].
  • 6. Department of General Surgery, Zhongshan City People's Hospital, Zhongshan, Guangdong Province, China. [email protected].
  • 7. Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. [email protected].
  • 8. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. [email protected].
  • 9. Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. [email protected].
  • 10. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. [email protected].
  • # Contributed equally.
PMID: 40328788 DOI: 10.1038/s41419-025-07690-1
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.

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