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GAS5通过促进E-钙黏蛋白来减弱胶质瘤干细胞样细胞的恶性进展。

GAS5 attenuates the malignant progression of glioma stem-like cells by promoting E-cadherin.

作者信息

Wang Haiyang, Wang Ding, Shen Yongfeng, Sun Chenglong, Hu Qiang, Jiang Li, Du Quan

机构信息

Department of Neurosurgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, P.R. China.

出版信息

Cancer Gene Ther. 2023 Mar;30(3):450-461. doi: 10.1038/s41417-022-00566-y. Epub 2022 Dec 2.

Abstract

It has been widely reported that glioma stem-like cells (GSCs) serve a crucial role in the malignant progression of glioma. In particular, recent studies have reported that long non-coding RNAs (lncRNAs) are closely associated with glioma development. However, the underlying molecular regulatory mechanistic role of GSCs remains poorly understood. The present study established two highly malignant glioma stem-like cell lines from clinical surgical specimens. In these, it was found that the lncRNA growth arrest-specific 5 (GAS5) expression was downregulated in GSCs and high-grade glioma tissues, compared with normal human astrocyte cells (NHAs) and normal brain tissues, respectively, which also showed a positive correlation with patient survival. Functional assays revealed that knocking down GAS5 expression promoted the proliferation, invasion, migration, stemness, and tumorigenicity of GSGs, while suppressing their apoptosis. Mechanistically, GAS5 directly sponged miR-23a, which in turn functioned as an oncogene by inhibiting E-cadherin, through the assays of reverse transcription-quantitative PCR (RT-qPCR) and luciferase reports. In addition, rescue experiments demonstrated that GAS5 could promote the expression and function of E-cadherin in a miR-23a-dependent manner. Collectively, these data suggest that GAS5 functions as a suppressor in GSCs by targeting the miR-23a/E-cadherin axis, which may be a promising therapeutic target against glioma.

摘要

已有广泛报道称,胶质瘤干细胞(GSCs)在胶质瘤的恶性进展中起关键作用。特别是,最近的研究报道长链非编码RNA(lncRNAs)与胶质瘤的发展密切相关。然而,GSCs潜在的分子调控机制作用仍知之甚少。本研究从临床手术标本中建立了两种高度恶性的胶质瘤干细胞系。在这些细胞系中发现,与正常人星形胶质细胞(NHAs)和正常脑组织相比,lncRNA生长停滞特异性5(GAS5)在GSCs和高级别胶质瘤组织中的表达分别下调,这也与患者生存率呈正相关。功能分析表明,敲低GAS5表达可促进GSGs的增殖、侵袭、迁移、干性和致瘤性,同时抑制其凋亡。机制上,通过逆转录定量PCR(RT-qPCR)和荧光素酶报告分析发现,GAS5直接吸附miR-23a,而miR-23a通过抑制E-钙黏蛋白发挥癌基因作用。此外,挽救实验表明,GAS5可以以miR-23a依赖的方式促进E-钙黏蛋白的表达和功能。总的来说,这些数据表明,GAS5通过靶向miR-23a/E-钙黏蛋白轴在GSCs中发挥抑制作用,这可能是一种有前景的抗胶质瘤治疗靶点。

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