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长链非编码RNA ZEB1-AS1促进胶质瘤的肿瘤发生并预示不良预后。

A Long Noncoding RNA ZEB1-AS1 Promotes Tumorigenesis and Predicts Poor Prognosis in Glioma.

作者信息

Lv Qiao-Li, Hu Lei, Chen Shu-Hui, Sun Bao, Fu Meng-Long, Qin Chong-Zhen, Qu Qiang, Wang Gui-Hua, He Chen-Jie, Zhou Hong-Hao

机构信息

Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China.

Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China.

出版信息

Int J Mol Sci. 2016 Aug 30;17(9):1431. doi: 10.3390/ijms17091431.

DOI:10.3390/ijms17091431
PMID:27589728
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5037710/
Abstract

Emerging studies show that long noncoding RNAs (lncRNAs) have important roles in carcinogenesis. lncRNA ZEB1 antisense 1 (ZEB1-AS1) is a novel lncRNA, whose clinical significance, biological function, and underlying mechanism remains unclear in glioma. Here, we found that ZEB1-AS1 was highly expressed in glioma tissues, being closely related to clinical stage of glioma. Moreover, patients with high ZEB1-AS1 levels had poor prognoses, with the evidence provided by multivariate Cox regression analysis indicating that ZEB1-AS1 expression could serve as an independent prognostic factor in glioma patients. Functionally, silencing of ZEB1-AS1 could significantly inhibit cell proliferation, migration, and invasion, as well as promote apoptosis. Knockdown of ZEB1-AS1 significantly induced the G0/G1 phase arrest and correspondingly decreased the percentage of S phase cells. Further analysis indicated that ZEB1-AS1 could regulate the cell cycle by inhibiting the expression of G1/S transition key regulators, such as Cyclin D1 and CDK2. Furthermore, ZEB1-AS1 functioned as an important regulator of migration and invasion via activating epithelial to mesenchymal transition (EMT) through up-regulating the expression of ZEB1, MMP2, MMP9, N-cadherin, and Integrin-β1 as well as decreasing E-cadherin levels in the metastatic progression of glioma. Additionally, forced down-regulation of ZEB1-AS1 could dramatically promote apoptosis by increasing the expression level of Bax and reducing Bcl-2 expression in glioma. Taken together, our data suggest that ZEB1-AS1 may serve as a new prognostic biomarker and therapeutic target of glioma.

摘要

新兴研究表明，长链非编码RNA（lncRNA）在肿瘤发生中发挥重要作用。lncRNA ZEB1反义RNA1（ZEB1-AS1）是一种新型lncRNA，其在胶质瘤中的临床意义、生物学功能及潜在机制尚不清楚。在此，我们发现ZEB1-AS1在胶质瘤组织中高表达，与胶质瘤的临床分期密切相关。此外，ZEB1-AS1水平高的患者预后较差，多因素Cox回归分析表明ZEB1-AS1表达可作为胶质瘤患者的独立预后因素。在功能上，沉默ZEB1-AS1可显著抑制细胞增殖、迁移和侵袭，并促进细胞凋亡。敲低ZEB1-AS1可显著诱导G0/G1期阻滞，并相应降低S期细胞百分比。进一步分析表明，ZEB1-AS1可通过抑制G1/S转换关键调节因子如细胞周期蛋白D1和细胞周期蛋白依赖性激酶2的表达来调节细胞周期。此外，在胶质瘤转移过程中，ZEB1-AS1通过上调ZEB1、基质金属蛋白酶2、基质金属蛋白酶9、N-钙黏蛋白和整合素-β1的表达以及降低E-钙黏蛋白水平，激活上皮-间质转化（EMT），从而作为迁移和侵袭的重要调节因子。此外，强制下调ZEB1-AS1可通过增加胶质瘤中Bax的表达水平和降低Bcl-2的表达来显著促进细胞凋亡。综上所述，我们的数据表明ZEB1-AS1可能作为胶质瘤的一种新的预后生物标志物和治疗靶点。

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