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

作者：Yu Zhang, Wei Su, Xiaoyu Ji, Yang Zhou, Qing Guan, Yuanxin Pang, Linkun Zhong, Yu Wang, Jun Xiang · 发表于：Cell Death and Disease · 年份：2025 · DOI：10.1038/s41419-025-07690-1 · 被引用次数：4 · 研究领域：Cellular transport and secretion、Microtubule and mitosis dynamics、Cancer-related Molecular Pathways

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.