Long Noncoding RNA NEAT1, Regulated by the EGFR Pathway, Contributes to Glioblastoma Progression Through the WNT/β-Catenin Pathway by Scaffolding EZH2
Long Noncoding RNA NEAT1, Regulated by the EGFR Pathway, Contributes to Glioblastoma Progression Through the WNT/β-Catenin Pathway by Scaffolding EZH2
复制标题
长非编码 RNA NEAT1，受 EGFR 通路调节，通过支架 EZH2 通过 WNT/β-Catenin 通路促进胶质母细胞瘤进展
DOI：
10.1158/1078-0432.ccr-17-0605
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发表时间：
2018-02-01
影响因子：
11.5
通讯作者：
Jiang, Chuanlu
中科院分区：
文献类型：
--
作者：
Chen, Qun;Cai, Jinquan;Jiang, Chuanlu
目的：长链非编码RNA与胶质瘤的发生有关，但其作用机制尚不清楚。通过公开的胶质瘤mRNA表达数据集，我们发现NEAT 1是一个潜在的癌基因。我们系统分析了NEAT 1在胶质母细胞瘤中的临床意义和作用机制。实验设计：首先，我们评估了NEAT 1的表达水平是否可以通过EGFR通路的活性来调节。我们随后评估了NEAT 1对WNT/β-连环蛋白通路及其靶结合基因的影响。结果：我们发现NEAT 1的表达受EGFR通路活性的调节，而EGFR通路下游的STAT 3和NF κ B（p65）介导了NEAT 1的表达。此外，我们发现NEAT 1通过增加β-连环蛋白核转运和下调ICAT、GSK 3B和Axin 2对胶质瘤细胞生长和侵袭至关重要。综上所述，我们发现NEAT 1可以与EZH 2结合并介导其启动子中H3 K27的三甲基化。NEAT 1耗竭也抑制GBM细胞的生长和侵袭在颅内animal model.Conclusions：EGFR/NEAT 1/EZH 2/β-catenin轴作为一个重要的效应器的肿瘤发生和发展，提示新的治疗方向胶质母细胞瘤。(C)2017年AACR。
Purpose: Long noncoding RNAs have been implicated in gliomagenesis, but theirmechanisms of action are mainly undocumented. Through public glioma mRNA expression data sets, we found that NEAT1 was a potential oncogene. We systematically analyzed the clinical significance and mechanism of NEAT1 in glioblastoma.Experimental Design: Initially, we evaluated whether NEAT1 expression levels could be regulated by EGFR pathway activity. We subsequently evaluated the effect of NEAT1 on the WNT/beta-catenin pathway and its target binding gene. The animal model supported the experimental findings.Results: We found that NEAT1 levels were regulated by EGFR pathway activity, which was mediated by STAT3 and NF kappa B (p65) downstream of the EGFR pathway. Moreover, we found that NEAT1 was critical for glioma cell growth and invasion by increasing beta-catenin nuclear transport and down-regulating ICAT, GSK3B, and Axin2. Taken together, we found that NEAT1 could bind to EZH2 and mediate the trimethylation of H3K27 in their promoters. NEAT1 depletion also inhibited GBM cell growth and invasion in the intracranial animal model.Conclusions: The EGFR/NEAT1/EZH2/beta-catenin axis serves as a critical effector of tumorigenesis and progression, suggesting new therapeutic directions in glioblastoma. (C) 2017 AACR.