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Long Noncoding RNA NHEG1 Drives β-Catenin Transactivation and Neuroblastoma Progression through Interacting with DDX5.
Molecular Therapy ( IF 12.1 ) Pub Date : 2020-01-11 , DOI: 10.1016/j.ymthe.2019.12.013 Xiang Zhao 1 , Dan Li 1 , Feng Yang 1 , Heng Lian 1 , Jianqun Wang 1 , Xiaojing Wang 2 , Erhu Fang 1 , Huajie Song 1 , Anpei Hu 1 , Yanhua Guo 1 , Yang Liu 1 , Hongjun Li 3 , Yajun Chen 3 , Kai Huang 2 , Liduan Zheng 4 , Qiangsong Tong 5
Molecular Therapy ( IF 12.1 ) Pub Date : 2020-01-11 , DOI: 10.1016/j.ymthe.2019.12.013 Xiang Zhao 1 , Dan Li 1 , Feng Yang 1 , Heng Lian 1 , Jianqun Wang 1 , Xiaojing Wang 2 , Erhu Fang 1 , Huajie Song 1 , Anpei Hu 1 , Yanhua Guo 1 , Yang Liu 1 , Hongjun Li 3 , Yajun Chen 3 , Kai Huang 2 , Liduan Zheng 4 , Qiangsong Tong 5
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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 of NHEG1 led to facilitated differentiation and decreased growth and aggressiveness of NB cells. Mechanistically, NHEG1 bound 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 that NHEG1 harbored oncogenic properties via its interplay with DDX5. Administration of small interfering RNAs against NHEG1 or DDX5 reduced tumor growth and prolonged survival of nude mice bearing xenografts. High NHEG1 or DDX5 expression was associated with poor survival of NB patients. These results indicate that lncRNA NHEG1 exhibits oncogenic activity that affects NB progression via stabilizing the DDX5 protein, which might serve as a potential therapeutic target for NB.
中文翻译：
长非编码RNA NHEG1通过与DDX5相互作用来驱动β-连环蛋白激活和神经母细胞瘤进展。
最近的研究表明，长的非编码RNA（lncRNA）在肿瘤进展中起着至关重要的作用。然而，lncRNAs在神经母细胞瘤（NB）中的功能作用和潜在机制仍然是难以捉摸的，神经母细胞瘤是儿童人群中最常见的恶性实体瘤。在这里，通过对公共RNA测序数据集的整合分析，高表达神经母细胞瘤1（NHEG1）被鉴定为与风险相关的lncRNA，导致NB的不良预后。NHEG1的耗尽导致NB细胞的分化加快，生长和侵略性下降。从机制上讲，NHEG1通过抑制蛋白酶体介导的降解与DEAD-box解旋酶5（DDX5）蛋白结合并使其稳定，从而导致β-catenin反式激活，从而改变了与NB进展相关的靶基因表达。我们进一步确定了具有正反馈回路的淋巴增强因子结合因子1（LEF1）/转录因子7样2（TCF7L2）/ NHEG1 / DDX5 /β-catenin轴，并证明NHEG1通过与DDX5相互作用而具有致癌性。对NHEG1或DDX5的小干扰RNA的管理减少了荷瘤裸鼠的肿瘤生长并延长了其存活时间。NHEG1或DDX5高表达与NB患者存活率低有关。这些结果表明，lncRNA NHEG1具有通过稳定DDX5蛋白影响NB进展的致癌活性，而DDX5蛋白可能是NB的潜在治疗靶标。
更新日期：2020-01-11
中文翻译：
长非编码RNA NHEG1通过与DDX5相互作用来驱动β-连环蛋白激活和神经母细胞瘤进展。
最近的研究表明，长的非编码RNA（lncRNA）在肿瘤进展中起着至关重要的作用。然而，lncRNAs在神经母细胞瘤（NB）中的功能作用和潜在机制仍然是难以捉摸的，神经母细胞瘤是儿童人群中最常见的恶性实体瘤。在这里，通过对公共RNA测序数据集的整合分析，高表达神经母细胞瘤1（NHEG1）被鉴定为与风险相关的lncRNA，导致NB的不良预后。NHEG1的耗尽导致NB细胞的分化加快，生长和侵略性下降。从机制上讲，NHEG1通过抑制蛋白酶体介导的降解与DEAD-box解旋酶5（DDX5）蛋白结合并使其稳定，从而导致β-catenin反式激活，从而改变了与NB进展相关的靶基因表达。我们进一步确定了具有正反馈回路的淋巴增强因子结合因子1（LEF1）/转录因子7样2（TCF7L2）/ NHEG1 / DDX5 /β-catenin轴，并证明NHEG1通过与DDX5相互作用而具有致癌性。对NHEG1或DDX5的小干扰RNA的管理减少了荷瘤裸鼠的肿瘤生长并延长了其存活时间。NHEG1或DDX5高表达与NB患者存活率低有关。这些结果表明，lncRNA NHEG1具有通过稳定DDX5蛋白影响NB进展的致癌活性，而DDX5蛋白可能是NB的潜在治疗靶标。
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