Department of Pathology & Shanxi Key Laboratory of Carcinogenesis and Translational Research on Esophageal Cancer, Shanxi Medical University, Taiyuan, Shanxi 030001 P. R. China.
College of Letter & Science, University of California Berkeley, Berkeley, California, USA.
Theranostics. 2020 Jan 1;10(4):1798-1813. doi: 10.7150/thno.38210. eCollection 2020.
: 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. : 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. : 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. : 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.
: 癌症基因组研究已经确定锌指蛋白 750（ZNF750）是食管鳞状细胞癌（ESCC）中一种新的显著突变基因。本研究旨在确定 ZNF750 在 ESCC 发展中的临床价值和分子机制。 : 利用 4 个已发表的 ESCC 队列的基因组数据分析 ZNF750 的突变谱。使用组织微阵列检测 308 例 ESCC 样本中的表达。进一步，在 ESCC 细胞中测试 ZNF750 对增殖、集落形成、迁移和侵袭的影响。PCR-array、染色质免疫沉淀（ChIP）、荧光素酶报告基因检测和挽救实验用于探索 ZNF750 的机制。在来自各种 SCC 类型的 TCGA 数据中分析 ZNF750 与其靶基因的相关性。 : ZNF750 在 ESCC 中频繁突变，最常见的类型是无义突变。ZNF750 在 ESCC 中的核/质比明显低于配对非肿瘤组织；它是 ESCC 患者独立的潜在生存预测因子。进一步，ZNF750 敲低显著促进 ESCC 细胞的增殖、集落形成、迁移和侵袭。PCR-array 显示上皮-间充质转化（EMT）是受 ZNF750 影响的主要生物学过程。此外，ZNF750 直接结合到 SNAI1 的启动子区域并抑制其活性。ZNF750 表达降低可上调 SNAI1 表达并促进 EMT 表型。SNAI1 敲低部分逆转了 ZNF750 敲低诱导的恶性表型。进一步的 TCGA 数据分析表明，在 ESCC 和其他 SCC 样本中，ZNF750 表达与 E-钙粘蛋白呈正相关，与 SNAI1、N-钙粘蛋白和波形蛋白呈负相关。 : 我们的结果表明，ZNF750 可能通过直接抑制 SNAI1 并抑制 EMT 过程在 ESCC 和其他类型的 SCC 中发挥肿瘤抑制因子的作用。
Zotero 插件
