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长链非编码 RNA TUG1 通过与 EZH2 相互作用抑制替莫唑胺耐药脑胶质瘤细胞的肿瘤干细胞样特性。

lncRNA TUG1 inhibits the cancer stem cell‑like properties of temozolomide‑resistant glioma cells by interacting with EZH2.

机构信息

Department of Neurosurgery, First People's Hospital of Kunming, Kunming, Yunnan 650032, P.R. China.

Department of Breast Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.

出版信息

Mol Med Rep. 2021 Jul;24(1). doi: 10.3892/mmr.2021.12172. Epub 2021 May 26.

Abstract

Temozolomide (TMZ) is currently one of the first‑line drugs used for the treatment of high‑grade gliomas. However, TMZ resistance results in unsatisfactory therapeutic effects in gliomas. Cancer stem cells (CSCs) have recently been determined to serve a pivotal regulatory role in tumor metastasis, recurrence and chemoresistance. In addition, numerous reports have shown that long non‑coding RNAs (lncRNAs) exert an essential role in the occurrence and development of tumors, and can be used as biomarkers for tumor diagnosis and treatment. Among them, studies have revealed that taurine upregulated gene 1 (TUG1) exhibits an important regulatory effect on the malignant biological behavior of glioma cells. Moreover, it has been reported that enhancer of Zeste homolog 2 polycomb repressive complex subunit 2 (EZH2) promotes tumorigenesis, including in glioma. However, the underlying mechanism of the interaction of TUG1 and EZH2 with CSCs of glioma remains elusive, and thus requires further clarification. The present study aimed to explore the role of TUG1 and EZH2 in TMZ resistance in glioma. Cell Counting Kit‑8, colony formation,sphere formation and Annexin V‑FITC/PI assays were used to detect the proliferation, clone formation efficiency, stemness and apoptosis of TMZ‑resistant glioma cells. Xenograft tumor assay was used to detect the effect of TUG1 on the tumorigenesis of TMZ‑resistant glioma cells. The present findings demonstrated that TUG1 exhibited a low expression in glioma cells, while EZH2 expression was the opposite. Moreover, it was observed that A172/TMZ cells possessed higher CSCs‑like properties compared with parent cells, and that TUG1 and EZH2 were abnormally expressed in A172/TMZ cells. Knockdown of TUG1 or overexpression of EZH2 promoted A172/TMZ cell proliferation and CSCs‑like properties, as well as inhibited their apoptosis, thereby enhancing the TMZ resistance of A172/TMZ cells. Furthermore, it was found that TUG1 alleviated the TMZ resistance of A172/TMZ cells by inhibiting EZH2 expression. Of note, overexpression of TUG1 inhibited the tumorigenicity of A172/TMZ cells by downregulating EZH2 expression in vivo. Collectively, the present study demonstrated that TUG1 served an essential regulatory role in TMZ resistance of gliomas.

摘要

替莫唑胺(TMZ)目前是治疗高级别神经胶质瘤的一线药物之一。然而,TMZ 耐药导致神经胶质瘤的治疗效果不理想。癌症干细胞(CSCs)最近被确定在肿瘤转移、复发和化疗耐药中发挥关键调节作用。此外,大量报道表明,长链非编码 RNA(lncRNA)在肿瘤的发生和发展中发挥着重要作用,并可作为肿瘤诊断和治疗的标志物。其中,研究表明牛磺酸上调基因 1(TUG1)对神经胶质瘤细胞的恶性生物学行为具有重要的调节作用。此外,有报道称,增强子的锌指蛋白 2 多梳抑制复合物亚单位 2(EZH2)促进肿瘤发生,包括神经胶质瘤。然而,TUG1 和 EZH2 与神经胶质瘤 CSCs 相互作用的潜在机制尚不清楚,因此需要进一步阐明。本研究旨在探讨 TUG1 和 EZH2 在神经胶质瘤 TMZ 耐药中的作用。细胞计数试剂盒-8、集落形成、球体形成和 Annexin V-FITC/PI 检测用于检测 TMZ 耐药神经胶质瘤细胞的增殖、克隆形成效率、干性和细胞凋亡。异种移植肿瘤实验用于检测 TUG1 对 TMZ 耐药神经胶质瘤细胞致瘤性的影响。本研究结果表明,TUG1 在神经胶质瘤细胞中表达较低,而 EZH2 的表达则相反。此外,观察到 A172/TMZ 细胞具有比亲本细胞更高的 CSCs 样特性,并且 TUG1 和 EZH2 在 A172/TMZ 细胞中异常表达。敲低 TUG1 或过表达 EZH2 促进 A172/TMZ 细胞增殖和 CSCs 样特性,并抑制其凋亡,从而增强 A172/TMZ 细胞对 TMZ 的耐药性。此外,研究发现 TUG1 通过抑制 EZH2 表达减轻 A172/TMZ 细胞的 TMZ 耐药性。值得注意的是,过表达 TUG1 通过下调 EZH2 表达抑制 A172/TMZ 细胞的致瘤性。综上所述,本研究表明 TUG1 在神经胶质瘤 TMZ 耐药中发挥重要调节作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2f8/8170197/2e7f8b0089b7/mmr-24-01-12172-g00.jpg

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