Long Noncoding RNA NHEG1 Drives β-Catenin Transactivation and Neuroblastoma Progression through Interacting with DDX5.
Long Noncoding RNA NHEG1 Drives β-Catenin Transactivation and Neuroblastoma Progression through Interacting with DDX5.
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DOI：
10.1016/j.ymthe.2019.12.013
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发表时间：
2020-01
期刊：
影响因子：
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通讯作者：
Xiangwang Zhao;Dan Li;Feng Yang;H. Lian;Jian-qun Wang;Xiaojing Wang;Erhu Fang;Huajie Song;
中科院分区：
文献类型：
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作者：
Xiangwang Zhao;Dan Li;Feng Yang;H. Lian;Jian-qun Wang;Xiaojing Wang;Erhu Fang;Huajie Song;
最近的研究表明，长链非编码RNA（lncRNA）在肿瘤进展中起着重要作用。然而，lncRNA在儿童人群中最常见的恶性实体肿瘤神经母细胞瘤（NB）中的功能作用和潜在机制仍然是难以捉摸的。在此，通过对公共RNA测序数据集的整合分析，神经母细胞瘤高表达1（NHEG 1）被鉴定为风险相关的lncRNA，导致NB的不利结果。NHEG 1的缺失促进NB细胞的分化，降低NB细胞的生长和侵袭性。从机制上讲，NHEG 1通过抑制蛋白酶体介导的降解结合并稳定DEAD-box解旋酶5（DDX 5）蛋白，导致β-连环蛋白反式激活，改变与NB进展相关的靶基因表达。我们进一步确定了淋巴增强子结合因子1（LEF 1）/转录因子7样2（TCF 7 L2）/NHEG 1/DDX 5/β-catenin轴的正反馈环，并证明NHEG 1通过与DDX 5的相互作用具有致癌特性。针对NHEG 1或DDX 5的小干扰RNA的施用减少了荷瘤裸鼠的肿瘤生长并延长了荷瘤裸鼠的存活。NHEG 1或DDX 5高表达与NB患者生存率低相关。这些结果表明，lncRNANHEG 1具有致癌活性，通过稳定DDX 5蛋白影响NB进展，这可能是NB的潜在治疗靶点。
Recent studies suggest that long noncoding RNAs (lncRNAs) play essential roles in tumor progression. However, the functional roles and underlying mechanisms of lncRNAs in neuroblastoma (NB), the most common malignant solid tumor in pediatric population, still remain elusive. Herein, through integrating analysis of a public RNA sequencing dataset, neuroblastoma highly expressed 1 (NHEG1) was identified as a risk-associated lncRNA, contributing to an unfavorable outcome of NB. Depletion ofNHEG1led to facilitated differentiation and decreased growth and aggressiveness of NB cells. Mechanistically,NHEG1bound to and stabilized DEAD-box helicase 5 (DDX5) protein through repressing proteasome-mediated degradation, resulting in β-catenin transactivation that altered target gene expression associated with NB progression. We further determined a lymphoid enhancer binding factor 1 (LEF1)/transcription factor 7-like 2 (TCF7L2)/NHEG1/DDX5/β-catenin axis with a positive feedback loop and demonstrated thatNHEG1harbored oncogenic properties via its interplay with DDX5. Administration of small interfering RNAs againstNHEG1orDDX5reduced tumor growth and prolonged survival of nude mice bearing xenografts. HighNHEG1or DDX5 expression was associated with poor survival of NB patients. These results indicate that lncRNANHEG1exhibits oncogenic activity that affects NB progression via stabilizing the DDX5 protein, which might serve as a potential therapeutic target for NB.