Zhang Yu, Su Wei, Ji Xiaoyu, Yang Zhou, Guan Qing, Pang Yuanxin, Zhong Linkun, Wang Yu, Xiang Jun
Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Cell Death Dis. 2025 May 6;16(1):362. doi: 10.1038/s41419-025-07690-1.
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.
尽管间变性甲状腺癌（ATC）仅占所有甲状腺恶性肿瘤的1%-2%，但其死亡率极高，占甲状腺癌相关死亡的14%-39%。在本研究中，我们确定了前蛋白转化酶枯草杆菌蛋白酶/九型凯新蛋白酶（PCSK9）在ATC进展中的关键作用。蛋白质组学分析表明，E-钙黏蛋白是PCSK9驱动的ATC恶性肿瘤的关键介质。从机制上讲，PCSK9通过溶酶体途径促进E-钙黏蛋白的降解。此外，p53功能的丧失，尤其是R248Q突变，在转录水平上解除了对PCSK9表达的抑制。值得注意的是，PCSK9抑制剂PF-846在体外和体内模型中均显著抑制了ATC的增殖和转移。总之，PCSK9通过溶酶体途径调节E-钙黏蛋白的降解来增强ATC的恶性程度，突出了其作为一个有前景的治疗靶点的潜力。
