Decreased ZNF750 promotes angiogenesis in a paracrine manner via activating DANCR/miR-4707-3p/FOXC2 axis in esophageal squamous cell carcinoma
Decreased ZNF750 promotes angiogenesis in a paracrine manner via activating DANCR/miR-4707-3p/FOXC2 axis in esophageal squamous cell carcinoma
复制标题
ZNF750 减少通过激活食管鳞状细胞癌中的 DANCR/miR-4707-3p/FOXC2 轴以旁分泌方式促进血管生成。
DOI：
10.1038/s41419-020-2492-2
复制
发表时间：
2020-04-27
影响因子：
9
通讯作者：
Cui, Yongping
中科院分区：
文献类型：
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作者：
Bi, Yanghui;Guo, Shixing;Cui, Yongping
ZNF 750是新一代测序技术在食管鳞状细胞癌中发现的一个新的显著突变基因。然而，其临床相关和潜在的机制仍然难以捉摸。通过对612例ESCC患者的基因组测序，我们分析了ZNF 750突变与临床病理特征的关系及其预后价值。我们进一步研究了ZNF 750在血管生成中的作用及其机制。结果显示ZNF 750基因突变/缺失与食管鳞癌的恶性进展和预后不良密切相关。ESCC细胞中ZNF 750的减少可诱导人脐静脉内皮细胞（HUVECs）和人动脉内皮细胞（HAECs）的血管生成增强，这种作用可能由FOXC 2间接介导。RNA-seq和ChIP显示lncRNA DANCR是ZNF 750的直接下游靶点。此外，敲低ZNF 750引起DANCR表达，其阻止miR-4707- 3 p以ceRNA方式与FOXC 2作为microRNA海绵相互作用，导致FOXC 2信号传导和血管生成增强。相反，ZNF 750表达逆转了该效应。我们的研究揭示了ZNF 750的新机制，强调了ZNF 750作为转移和预后生物标志物的重要性，并为携带ZNF 750突变的ESCC患者提供了潜在的治疗靶点。
ZNF750 is one novel significantly mutated gene identified in esophageal squamous cell carcinoma (ESCC) using next-generation sequencing. However, its clinically relevant and potential mechanisms have remained elusive. Using genomic sequencing of 612 ESCC patients, we analyzed the associations of ZNF750 mutations with clinicopathologic features and its prognostic value. We further investigated the function and underlying mechanism of ZNF750 in angiogenesis. The results showed ZNF750 mutations/deletions are significantly associated with malignant progression and poor prognosis of ESCC patients. Decreased ZNF750 in ESCC cells induces enhanced angiogenesis of human umbilical vein endothelial cells (HUVECs) and human arterial endothelial cells (HAECs), and the effect may be indirectly mediated by FOXC2. RNA-seq and ChIP shows lncRNA DANCR is a direct downstream target of ZNF750. Furtherly, knockdown ZNF750 evokes DANCR expression, which prevents miR-4707-3p to interact with FOXC2 as a microRNA sponge in a ceRNA manner, leading to enhanced FOXC2 signaling and angiogenesis. In contrast, ZNF750 expression reverses the effect. Our study reveals a novel mechanism of ZNF750, highlights a significance of ZNF750 as a metastatic and prognostic biomarker, and offers potential therapeutic targets for ESCC patients harboring ZNF750 mutations.