CDD|王卓颖团队揭示LncRNA-MIAT/miR-150-5p/EZH2轴在甲状腺癌中的作用机制

2022年8月4日 0条评论 372次阅读 0人点赞

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长链非编码RNA（lncRNA）在人类癌症中发挥重要作用，但仍对它们在甲状腺乳头状癌（PTC）中的作用知之甚少。2021年11月22日，上海交通大学医学院附属仁济医院头颈外科王卓颖团队在Cell Death & Disease上发表了题为“LncRNA-MIAT promotes thyroid cancer progression and function as ceRNA to target EZH2 by sponging miR-150-5p”的研究论文。本研究的目的是使用全基因组表达谱来识别在PTC中充当竞争性内源RNA（ceRNA）的lncRNA。团队基于lncRNA微阵列数据构建了一个ceRNA网络，并通过体外和体内实验验证了心肌梗死相关转录物lncRNA MIAT、miRNA-150-5p和EZH2之间的相关性。研究结果表明MIAT可能通过miR-150/EZH2通路抑制EZH2表达并促进PTC细胞侵袭，至此，团队认为MIAT可作为有价值的PTC预后生物标志物和治疗靶点。

PTC是最常见的内分泌恶性肿瘤，其全球发病率迅速上升。研究表明，基因组不稳定性或表观遗传标志物改变导致的基因表达失调在PTC中起主要作用。近年来，竞争性内源性RNA（ceRNA）假说引起了科研人员的广泛关注，该假说描述了一个由microRNA（miRNA）介导的复杂转录后调控网络：通过共享一个或多个miRNA反应元件（MRE），mRNA和lncRNA竞争与miRNA的结合，从而在功能上影响受miRNA调控的mRNA。

在这项研究中，团队首先假设PTC和正常甲状腺组织之间仍存在大量以前未探索的遗传差异，尤其是在lncRNA表达模式方面。接下来在该假设的基础上，团队通过lncRNA微阵列分析了PTC肿瘤和非肿瘤组织样本中差异表达的lncRNA，然后，从公共数据库收集miRNA和mRNA表达数据，构建lncRNA–microRNA–mRNA调控网络，结果发现了15个lncRNAs、28个miRNAs和数百个参与ceRNA网络的mRNAs，进一步的，团队在TCGA数据中发现lncRNA MIAT和EZH2在癌症类型中的表达之间存在极好的正相关，并且，在各种临床病理特征中MIAT/EZH2表达存在显著差异。至此，团队通过结合临床特征的相关性鉴定了关键的lncRNA MIAT，因此，团队接下来通过体外和体内实验对其功能进行了验证。

首先，关键的功能获得和功能缺失实验表明MIAT在体外抑制细胞增殖和迁移；其次，在PTC细胞中EZH2被确定为miR-150-5p的直接下游靶标；此外，回补实验证明，EZH2表达的恢复部分消除了miR-150-5p的生物学效应；再者，MIAT的过表达与miR-150-5p表达呈负相关。综上所述，通过构建lncRNA-miRNA-mRNA网络，团队发现lncRNA MIAT可能通过与miR-150-5p的相互作用调节EZH2信号，进而在PTC的发生发展中发挥重要作用。

《CDD|王卓颖团队揭示LncRNA-MIAT/miR-150-5p/EZH2轴在甲状腺癌中的作用机制》

图 MIAT对PTC细胞的生物学调控分子机制假设示意图。

期刊及DOI号

Cell Death Dis. 2021 Nov 22.

doi: 10.1038/s41419-021-04386-0.

题目

LncRNA-MIAT promotes thyroid cancer progression and function as ceRNA to target EZH2 by sponging miR-150-5p

摘要

While long noncoding RNAs (lncRNAs) have been reported to play an important role in human cancer types, they remain poorly understood in papillary thyroid carcinoma (PTC). The aim of this study was to use genome-wide expression profiling to identify lncRNAs acting as competing endogenous RNAs (ceRNAs) in PTC. We constructed a ceRNA network based on our lncRNA microarray data and validated the correlation between myocardial infarction-associated transcript lncRNA (MIAT), miRNA-150-5p, and EZH2 in vitro and in vivo. We found 15 lncRNAs, 28 miRNAs, and hundreds of mRNAs involved in this ceRNA network. Splendid positive correlations were found between the MIAT and EZH2 expression in types of cancer in TCGA data. Besides, significant differences in MIAT/EZH2 expression were found among various clinicopathological features. Gain- and loss-of-function experiments revealed that MIAT inhibited cell proliferation and migration in vitro. Moreover, EZH2 was identified as a direct downstream target of miR-150-5p in PTC cells. Restoration of EZH2 expression partially abolished the biological effects of miR-150-5p. Furthermore, overexpression of MIAT was inversely correlated with miR-150-5p expression. Knockdown of MIAT produced significant behavioral alter maybe partly due to the function of the MIAT-150-5p-EZH2 network. Our findings suggest MIAT may inhibit EZH2 expression and promote PTC cell invasion via the miR-150/EZH2 pathway. Therefore, MIAT may serve as a valuable prognostic biomarker and therapeutic target for PTC.