Zhao Zhang, Ding Fadian, Zhang Zhibo
Department of Hepatopancreatobiliary Surgery, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China.
Department of Hepatopancreatobiliary Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China.
APMIS. 2025 Aug;133(8):e70060. doi: 10.1111/apm.70060.
Hepatocellular carcinoma (HCC) is an aggressive malignancy with poor prognosis, frequent metastasis, and therapy resistance. Epithelial-mesenchymal transition (EMT) and aberrant Wnt/β-catenin signaling are key drivers of HCC progression. Secreted frizzled-related protein 5 (SFRP5), a Wnt/β-catenin signaling antagonist, has been implicated in various cancers, but its role in HCC remains unclear. This study explores the regulatory interactions between SFRP5, EMT, and Wnt/β-catenin signaling in HCC. Bioinformatics analysis, patient-derived tissue samples, and in vitro experiments revealed significant downregulation of SFRP5 due to promoter hypermethylation. Methylation-specific PCR confirmed extensive SFRP5 methylation, while treatment with 5-Aza-2'-deoxycytidinerestored SFRP5 expression, suppressing Wnt/β-catenin signaling and EMT. Functional assays demonstrated that SFRP5 overexpression inhibited HCC cell proliferation, migration, and colony formation while promoting apoptosis. Western blot and immunofluorescence confirmed that SFRP5 restoration suppressed β-catenin and its targets (MYC, Cyclin D1, Survivin), increased E-cadherin, and decreased mesenchymal markers (Vimentin, Fibronectin, Twist). In vivo xenograft models showed that SFRP5 overexpression reduced tumor growth and EMT marker expression. These findings highlight SFRP5 as a tumor suppressor in HCC, where epigenetic silencing promotes tumor progression via Wnt/β-catenin signaling activation. Targeting SFRP5 methylation may provide a novel therapeutic strategy for HCC.
肝细胞癌（HCC）是一种侵袭性恶性肿瘤，预后差、转移频繁且具有治疗抗性。上皮-间质转化（EMT）和异常的Wnt/β-连环蛋白信号传导是HCC进展的关键驱动因素。分泌型卷曲相关蛋白5（SFRP5）是一种Wnt/β-连环蛋白信号拮抗剂，已被认为与多种癌症有关，但其在HCC中的作用仍不清楚。本研究探讨了SFRP5、EMT和Wnt/β-连环蛋白信号传导在HCC中的调控相互作用。生物信息学分析、患者来源的组织样本和体外实验显示，由于启动子高甲基化，SFRP5显著下调。甲基化特异性PCR证实了广泛的SFRP5甲基化，而用5-氮杂-2'-脱氧胞苷处理可恢复SFRP5表达，抑制Wnt/β-连环蛋白信号传导和EMT。功能试验表明，SFRP5过表达抑制HCC细胞增殖、迁移和集落形成，同时促进细胞凋亡。蛋白质印迹法和免疫荧光法证实，SFRP5的恢复抑制了β-连环蛋白及其靶标（MYC、细胞周期蛋白D1、生存素），增加了E-钙黏蛋白，并降低了间充质标志物（波形蛋白、纤连蛋白、Twist）。体内异种移植模型显示，SFRP5过表达减少了肿瘤生长和EMT标志物表达。这些发现突出了SFRP5作为HCC中的一种肿瘤抑制因子，其中表观遗传沉默通过Wnt/β-连环蛋白信号激活促进肿瘤进展。靶向SFRP5甲基化可能为HCC提供一种新的治疗策略。
