Identification of miRNA signature associated with BMP2 and chemosensitivity of TMZ in glioblastoma stem-like cells
Identification of miRNA signature associated with BMP2 and chemosensitivity of TMZ in glioblastoma stem-like cells
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DOI：
10.1016/j.gendis.2019.09.002
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发表时间：
2020-09-01
期刊：
影响因子：
6.8
通讯作者：
Li, Ying
中科院分区：
文献类型：
--
作者：
Guo, Xiaoyu;Luo, Ziguo;Li, Ying
多形性胶质母细胞瘤(GBM)是成人最致命的颅内肿瘤。胶质母细胞瘤干细胞(GSCs)与肿瘤的发生和化疗耐药有关。已知BMP可增加GSCs对替莫唑胺(TMZ)的反应，然而，其细胞内分子机制仍不清楚。在本研究中，我们建立了一个称为U87S的GSC细胞模型，并进行了RNA测序，以确定BMP2、TMZ或BMP2和TMZ联合处理的U875细胞的差异表达(DE)miRNA图谱。生物信息学分析表明，大多数DE miRNAs参与了癌症的通路，表明它们在胶质瘤形成中发挥了关键作用。对来自RNA-seq的8个miRNAs进行了验证。其中4个miRNAs(Has-miR-199a-3p、hsa-miR-374B-5p、hsa-miR-320d和hsa-miR-339-5p)在GBM肿瘤组织中显著上调。其中hsa-miR-199a-3p与GBM患者的生存密切相关，并在U875细胞中有差异表达。BMP可上调hsa-miR-199a-3p的表达。在U875细胞中过表达hsa-miR-199a-3p可抑制细胞活力，增强TMZ的细胞毒作用。BMP的激活增强了hsa-miR-199a-3p对细胞活力和TMZ介导的细胞毒作用的影响。此外，对hsa-miR-199a-3p的5个预测靶点的表达进行了评估。其中4例在基底膜肿瘤中有差异表达。其中一个基因SLC22A18与GBM患者的生存相关。最后，构建了hsa-miR-199a-3p介导的CENA网络，为以后的研究提供了方便。总之，我们的数据提供了与GSCs中BMP2和TMZ相关的DE miRNA表达谱，这可能会导致找到专门针对GSCs的基于miRNA的靶向疗法。版权所有(C)2019，重庆医科大学。爱思唯尔B.V.制作和主办。
Glioblastoma multiform (GBM) is the most lethal intracranial tumor in adults. Glioblastoma stem-like cells (GSCs) are responsible for tumorigenesis and chemotherapy resistance. BMPs are known to increase temozolomide (TMZ) response in GSCs, however, the intracellular molecular mechanism remains largely unknown. In this study, we built a GSC cell model called U87S, and performed RNA sequencing to identify differentially expressed (DE) miRNA profiles in U875 cells treated with BMP2, TMZ or combined BMP2 and TMZ respectively. Bioinformatics analysis revealed that most DE miRNAs were involved in the cancer pathways, suggesting their crucial roles in gliomagenesis. Eight miRNAs from RNA-seq were validated. Four out of these miRNAs (has-miR-199a-3p, hsa-miR-374b-5p, hsa-miR-320d, and hsa-miR-339-5p) were found significantly up-regulated in GBM tumor tissues. One of them, hsa-miR-199a-3p, was significantly correlated with the survival of GBM patients, and differentially expressed in U875 cells. Expression of hsa-miR-199a-3p was up-regulated by BMP. Overexpression of hsa-miR-199a-3p in U875 cells inhibited cell viability and enhanced the cytotoxicity of TMZ. And activation of BMP boosted the effect of hsa-miR-199a-3p on cell viability and TMZ-mediated cytotoxicity. Besides, expressions of five predicted targets of hsa-miR-199a-3p were evaluated. Four of them were differentially expressed in GBM tumors. And one of them, SLC22A18, was associated with the survival of GBM patients. In the end, a hsa-miR-199a-3p-mediated ceRNA network was constructed for the convenience of future study. Together, our data provided DE miRNA expression profiles associated with BMP2 and TMZ in GSCs, which might lead to finding out miRNA-based target therapies that specially target GSCs. Copyright (C) 2019, Chongqing Medical University. Production and hosting by Elsevier B.V.