Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China.
Cerebral Vascular Disease Research Center, Anhui Medical University, Hefei, 230601, China.
J Exp Clin Cancer Res. 2021 Oct 25;40(1):337. doi: 10.1186/s13046-021-02129-9.
Long non-coding RNAs (lncRNAs) have been considered as one type of gene expression regulator for cancer development, but it is not clear how these are regulated. This study aimed to identify a specific lncRNA that promotes glioma progression.
RNA sequencing (RNA-seq) and quantitative real-time PCR were performed to screen differentially expressed genes. CCK-8, transwell migration, invasion assays, and a mouse xenograft model were performed to determine the functions of TMEM44-AS1. Co-IP, ChIP, Dual-luciferase reporter assays, RNA pulldown, and RNA immunoprecipitation assays were performed to study the molecular mechanism of TMEM44-AS1 and the downstream target.
We identified a novel lncRNA TMEM44-AS1, which was aberrantly expressed in glioma tissues, and that increased TMEM44-AS1 expression was correlated with malignant progression and poor survival for patients with glioma. Expression of TMEM44-AS1 increased the proliferation, colony formation, migration, and invasion of glioma cells. Knockdown of TMEM44-AS1 in glioma cells reduced cell proliferation, colony formation, migration and invasion, and tumor growth in a nude mouse xenograft model. Mechanistically, TMEM44-AS1 is directly bound to the SerpinB3, and sequentially activated Myc and EGR1/IL-6 signaling; Myc transcriptionally induced TMEM44-AS1 and directly bound to the promoter and super-enhancer of TMEM44-AS1, thus forming a positive feedback loop with TMEM44-AS. Further studies demonstrated that Myc interacts with MED1 regulates the super-enhancer of TMEM44-AS1. More importantly, a novel small-molecule Myc inhibitor, Myci975, alleviated TMEM44-AS1-promoted the growth of glioma cells.
Our study implicates a crucial role of the TMEM44-AS1-Myc axis in glioma progression and provides a possible anti-glioma therapeutic agent.
长链非编码 RNA（lncRNA）被认为是癌症发展的一种基因表达调控因子，但这些调控因子的调控机制尚不清楚。本研究旨在鉴定一种促进神经胶质瘤进展的特定 lncRNA。
采用 RNA 测序（RNA-seq）和实时定量 PCR 筛选差异表达基因。通过 CCK-8 法、transwell 迁移、侵袭实验和小鼠异种移植模型来确定 TMEM44-AS1 的功能。通过 Co-IP、ChIP、双荧光素酶报告基因检测、RNA 下拉和 RNA 免疫沉淀实验来研究 TMEM44-AS1 及其下游靶基因的分子机制。
我们鉴定了一种新型 lncRNA TMEM44-AS1，其在神经胶质瘤组织中异常表达，并且 TMEM44-AS1 表达的增加与神经胶质瘤患者的恶性进展和不良预后相关。TMEM44-AS1 的表达增加了神经胶质瘤细胞的增殖、集落形成、迁移和侵袭。在神经胶质瘤细胞中敲低 TMEM44-AS1 可降低细胞增殖、集落形成、迁移和侵袭以及裸鼠异种移植模型中的肿瘤生长。机制上，TMEM44-AS1 直接与 SerpinB3 结合，随后激活 Myc 和 EGR1/IL-6 信号通路；Myc 转录激活 TMEM44-AS1，并直接结合 TMEM44-AS1 的启动子和超级增强子，从而与 TMEM44-AS 形成正反馈回路。进一步的研究表明，Myc 与 MED1 相互作用调节 TMEM44-AS1 的超级增强子。更重要的是，一种新型的 Myc 小分子抑制剂 Myci975 可减轻 TMEM44-AS1 促进神经胶质瘤细胞生长的作用。
本研究表明 TMEM44-AS1-Myc 轴在神经胶质瘤进展中起关键作用，并为神经胶质瘤的治疗提供了一种潜在的药物。
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