Department of Neurosurgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, China.
Institute of Chengdu Biology, Sichuan Translational Medicine Hospital, Chinese Academy of Sciences, Chengdu 610072, Sichuan, China.
Aging (Albany NY). 2020 Oct 21;12(20):20285-20307. doi: 10.18632/aging.103800.
Glioma is one of the most commonly diagnosed brain malignancies with a high cancer-related death rate in humans. The prognosis of glioma patients is still unsatisfactory. In the present study, we attempted to identify lncRNAs and miRNAs that might be related to NF-κB-mediated epithelial-mesenchymal transition in glioma cells based on online microarray expression profiles, and investigate the specific effects of lncRNA-miRNA-mRNA axes on glioma cell phenotypes. Herein, we identified lncRNA DGCR5 as a downregulated lncRNA in glioma that was negatively regulated by NF-κB1 in an NF-κB1 RE-dependent manner. LncRNA DGCR5 overexpression significantly inhibited the capacity of glioma cells to proliferate, migrate, and invade, whereas promoted the apoptosis of glioma cells. Moreover, lncRNA DGCR5 overexpression upregulated the epithelial marker E-cadherin while downregulating the mesenchymal marker VIM, as well as Snai2 and TWIST. Regarding the underlying molecular mechanisms, lncRNA DGCR5 could inhibit miR-21 and miR-23a expression, and miR-21 or miR-23a overexpression significantly reversed the tumor-suppressive effects of lncRNA DGCR5 overexpression. LncRNA DGCR5 exerted its tumor-suppressive effects through the DGCR5/miR-21/Smad7 and DGCR5/miR-23a/PTEN axes. In conclusion, lncRNA DGCR5 suppresses the capacity of glioma cells to migrate and invade via miR-21/Smad7, whereas it inhibits the proliferation and enhances the apoptosis of glioma cells through miR-23a/PTEN.
神经胶质瘤是最常见的脑恶性肿瘤之一,其在人类中的癌症相关死亡率较高。神经胶质瘤患者的预后仍然不理想。在本研究中,我们试图根据在线微阵列表达谱,鉴定可能与 NF-κB 介导的神经胶质瘤细胞上皮-间充质转化相关的 lncRNA 和 miRNA,并研究 lncRNA-miRNA-mRNA 轴对神经胶质瘤细胞表型的具体影响。在此,我们鉴定出 lncRNA DGCR5 是一种在神经胶质瘤中下调的 lncRNA,它受 NF-κB1 的负调控,NF-κB1 以 NF-κB1 RE 依赖的方式调控其表达。lncRNA DGCR5 的过表达显著抑制神经胶质瘤细胞的增殖、迁移和侵袭能力,而促进神经胶质瘤细胞的凋亡。此外,lncRNA DGCR5 的过表达上调上皮标志物 E-钙黏蛋白,而下调间充质标志物 VIM、Snai2 和 TWIST。关于潜在的分子机制,lncRNA DGCR5 可以抑制 miR-21 和 miR-23a 的表达,而 miR-21 或 miR-23a 的过表达显著逆转了 lncRNA DGCR5 过表达的肿瘤抑制作用。lncRNA DGCR5 通过 DGCR5/miR-21/Smad7 和 DGCR5/miR-23a/PTEN 轴发挥其肿瘤抑制作用。总之,lncRNA DGCR5 通过 miR-21/Smad7 抑制神经胶质瘤细胞迁移和侵袭的能力,而通过 miR-23a/PTEN 抑制神经胶质瘤细胞的增殖并增强其凋亡。