CARM1-induced lncRNA NEAT1 synchronously activates MYCN and GalNAcT-I to accelerate the progression of neuroblastoma.

IF 2.6 3区生物学 Q2 GENETICS & HEREDITY

Gene Pub Date : 2025-02-20 Epub Date: 2024-12-14 DOI:10.1016/j.gene.2024.149164

Zhigang Hu, Weili Xu, Huiming Wang, Meng Li, Juan Wang, Chi Sun, Xiaofeng Yang

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引用次数: 0

Abstract

Purpose: Long non-coding RNAs (lncRNAs) play important roles in progression of neuroblastoma (NB). LncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) has been shown to affect the development of multiple tumors. However, the effect of NEAT1 on NB remain unclear. In this study, the new mechanisms whereby how NEAT1 influences tumor progression in NB was investigated.

Methods: RT-qPCR, western blot, bioinformatics, cell growth, Transwell, and flow cytometric analyses were performed to determine how NEAT1 synchronously regulates the miR-873-5p/MYCN proto-oncogene(MYCN) and miR-873-5p/polypeptide N-acetylgalactosaminyltransferase 1(GalNAcT-I) axes to accelerate the progression of NB. NB-bearing animal models were established to evaluate the function of NEAT1 in NB. The relationships between transcription factor coactivatorassociated arginine methyltransferase 1 (CARM1) and NEAT1, NEAT1 and miR-873-5p, miR-873-5p and GalNacT-I or MYCN, were verified using luciferase reporter gene assay, respectively.

Results: Our study revealed elevated levels of NEAT1 expression in NB cells and tissues which was associated with an advanced pathological stage and poor prognostic outcomes. According to in vitro gain- and loss- of function experiments, NEAT1 enhances progression of NB. NEAT1 silencing was found to inhibit NB proliferation in vivo. Mechanistically, to achieve upstream regulation, epigenetic downregulation of NEAT1 was achieved via the inhibition of CARM1. NEAT1 was found to positively regulate MYCN and GalNAcT-I levels as a competitive sponge of miR-873-5p.

Conclusion: Activity of the lncRNA NEAT1 can be triggered via CARM1, which synchronously promotes NB development via the miR-873-5p/MYCN and miR-873-5p/GalNAcT-I axes. These findings shed light on the novel molecular mechanisms underlying NB progression.

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CARM1诱导的lncRNA NEAT1可同步激活MYCN和GalNAcT-I，从而加速神经母细胞瘤的进展。

目的：长链非编码rna （lncRNAs）在神经母细胞瘤（NB）的发生发展中起重要作用。LncRNA核旁斑组装转录本1 （NEAT1）已被证明影响多种肿瘤的发展。然而，NEAT1对NB的影响尚不清楚。在这项研究中，研究了NEAT1影响NB肿瘤进展的新机制。方法：通过RT-qPCR、western blot、生物信息学、细胞生长、Transwell和流式细胞术分析，确定NEAT1如何同步调节miR-873-5p/MYCN原癌基因（MYCN）和miR-873-5p/多肽n -乙酰半乳糖胺基转移酶1（GalNAcT-I）轴，加速NB的进展。建立带NB动物模型，评价NEAT1在NB中的功能。转录因子共激活因子相关精氨酸甲基转移酶1 （CARM1）与NEAT1、NEAT1与miR-873-5p、miR-873-5p与GalNacT-I或MYCN之间的关系分别通过荧光素酶报告基因测定验证。结果：我们的研究显示NB细胞和组织中NEAT1表达水平升高与晚期病理阶段和不良预后相关。根据体外功能增益和损失实验，NEAT1促进NB的进展。NEAT1沉默可抑制NB在体内的增殖。从机制上讲，为了实现上游调控，NEAT1的表观遗传下调是通过抑制CARM1实现的。NEAT1作为miR-873-5p的竞争海绵，正调节MYCN和GalNAcT-I水平。结论：lncRNA NEAT1的活性可以通过CARM1触发，CARM1通过miR-873-5p/MYCN和miR-873-5p/GalNAcT-I轴同步促进NB的发展。这些发现揭示了NB进展的新分子机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Gene 生物-遗传学

CiteScore

6.10

自引率

2.90%

发文量

718

审稿时长

42 days

期刊介绍： Gene publishes papers that focus on the regulation, expression, function and evolution of genes in all biological contexts, including all prokaryotic and eukaryotic organisms, as well as viruses.