Novel ESCC-related gene ZNF750 as potential Prognostic biomarker and inhibits Epithelial-Mesenchymal Transition through directly depressing SNAI1 promoter in ESCC
Novel ESCC-related gene ZNF750 as potential Prognostic biomarker and inhibits Epithelial-Mesenchymal Transition through directly depressing SNAI1 promoter in ESCC
复制标题
新型 ESCC 相关基因 ZNF750 作为潜在的预后生物标志物，并通过直接抑制 ESCC 中的 SNAI1 启动子来抑制上皮-间质转化
DOI：
10.7150/thno.38210
复制
发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Cui, Yongping
中科院分区：
文献类型：
--
作者：
Kong, Pengzhou;Xu, Enwei;Cui, Yongping
背景资料：锌指蛋白750（ZNF 750）是一个在食管鳞状细胞癌（ESCC）中发生显著突变的新基因。本研究旨在探讨ZNF 750在食管鳞癌发生发展中的作用及其分子机制。方法：采用4个已报道的食管鳞癌队列的基因组数据，分析ZNF 750的突变谱。应用组织芯片技术检测308例食管鳞癌组织中该基因的表达。进一步观察ZNF 750对ESCC细胞增殖、集落形成、迁移和侵袭能力的影响。采用PCR芯片、染色质免疫沉淀（ChIP）、荧光素酶报告基因分析和拯救分析等方法探讨ZNF 750的作用机制。在不同类型SCC的TCGA数据中分析ZNF 750与其靶基因的相关性。结果：ZNF 750基因在食管鳞癌中突变频率较高，以无义突变最常见。其在ESCC中的细胞核/细胞质比显著低于配对的非肿瘤组织;它是ESCC患者生存的独立和潜在的预测因子。ZNF 750基因敲减可显著促进ESCC细胞的增殖、集落形成、迁移和侵袭。PCR芯片显示上皮细胞向间质细胞转化（EMT）是ZNF 750影响的主要生物学过程。此外，ZNF 750直接结合到SNAI 1的启动子区并抑制其活性。ZNF 750表达减少可上调SNAI 1表达，促进EMT表型。SNAI 1基因敲减可部分逆转ZNF 750基因敲减诱导的恶性表型。进一步的TCGA数据分析显示，ZNF 750在ESCC和其他SCC中的表达与E-cadherin呈正相关，与SNAI 1、N-cadherin和Vimentin呈负相关。结论：我们的研究结果表明，ZNF 750可能通过直接抑制SNAI 1和抑制EMT过程在ESCC和其他类型的SCC中发挥抑癌作用。
Background: Cancer genomic studies have identified Zinc Finger Protein 750 (ZNF750) was a novel significantly mutated gene in esophageal squamous cell carcinoma (ESCC). This study was designed to determine the clinical value and molecular mechanisms of ZNF750 in the development of ESCC. Methods: Genomic data from 4 reported ESCC cohorts were used to analyze the mutation profile of ZNF750. Tissue microarrays were used to detect its expression in 308 ESCC samples. Furtherly, the effects of ZNF750 on proliferation, colony formation, migration and invasion were tested in ESCC cells. PCR-array, chromatin immunoprecipitation (ChIP), luciferase reporter assays, and rescue assay were used to explore the mechanism of ZNF750. Correlation of ZNF750 with its target genes was analyzed in TCGA data from various SCC types. Results: ZNF750 was frequently mutated in ESCC and the most common type was nonsense mutation. Its nucleus/cytoplasm ratio in ESCC was significantly lower than that in paired non-tumor tissues; it was an independent and potential predictor for survival in ESCC patients. Furtherly, ZNF750 knockdown significantly promoted proliferation, colony formation, migration and invasion in ESCC cells. PCR-array showed epithelial-to-mesenchymal transition (EMT) was the main biologic process affected by ZNF750. Moreover, ZNF750 directly bound to the promoter region of SNAI1 and depressed its activity. Decreased ZNF750 up-regulated SNAI1 expression and promoted EMT phenotype. SNAI1 knockdown partially reversed the malignant phenotype induced by ZNF750 knockdown. Further TCGA data analyses showed ZNF750 expression was positively correlated with E-cadherin and negatively correlated with SNAI1, N-cadherin and Vimentin in ESCC and other SCC samples. Conclusion: Our results suggest that ZNF750 may act as a tumor suppressor by directly repressing SNAI1 and inhibiting EMT process in ESCC and other types of SCC.