The lack of meaningful and effective early-stage markers remains the major challenge in the diagnosis of gallbladder cancer (GBC) and a huge barrier to timely treatment. Zinc finger protein 64 (ZFP64), a member of the zinc finger protein family, is considered to be a promising predictor in multiple tumors, but its potential effect in GBC still remains unclear. Here, we identified that ZFP64 was a vital regulatory protein in GBC. We found that ZFP64 expressed higher in GBC gallbladder carcinoma tissues than in normal tissues and was positively correlated with poor prognosis. Furthermore, ZFP64 was responsible for the migration, invasion, proliferation, anti-apoptosis, and epithelial mesenchymal transition (EMT) of GBC cells in vitro and in vivo. Mechanistically, through Co-IP assay, we confirmed that ZFP64 recruits HDAC1 localized to the promoter region ofNUMBfor deacetylation and therefore inhibitsNUMBexpression. The downregulation of NUMB enhanced the activation of the Notch1 signaling pathway, which is indispensable for the GBC-promotion effect of ZFP64 on GBC. In conclusion, ZFP64 regulated GBC progression and metastasis through upregulating the Notch1 signaling pathway, and thus ZFP64 is expected to become a new focus for a GBC prognostic marker and targeted therapy.
缺乏有效且具有临床意义的早期标志物，仍然是胆囊癌（GBC）诊断中的主要挑战，也是实现及时治疗的巨大障碍。锌指蛋白64（ZFP64）作为锌指蛋白家族成员，在多种肿瘤中被认为是一种有前景的预测因子，但其在GBC中的潜在作用尚不明确。本研究证实ZFP64是GBC中的一个关键调控蛋白。我们发现ZFP64在GBC癌组织中的表达高于正常组织，且与不良预后呈正相关。此外，ZFP64在体内外实验中均能促进GBC细胞的迁移、侵袭、增殖、抗凋亡及上皮间质转化（EMT）。机制上，通过免疫共沉淀实验，我们证实ZFP64可招募HDAC1定位于NUMB基因启动子区域使其去乙酰化，从而抑制NUMB的表达。NUMB的下调增强了Notch1信号通路的激活，而该通路对于ZFP64促进GBC的发展至关重要。综上所述，ZFP64通过上调Notch1信号通路调控GBC的进展和转移，因此ZFP64有望成为GBC预后标志物和靶向治疗的新焦点。
肿瘤(癌症)患者之家