Department of Neurosurgery, Shanghai Fifth People's Hospital, Fudan University, No.801, Heqing Road, Minhang District, Shanghai, 200240, China.
Neurotox Res. 2022 Oct;40(5):1152-1162. doi: 10.1007/s12640-022-00536-0. Epub 2022 Jul 29.
Glioblastoma (GBM) is the most prevalent primary cerebral tumor in adults with high aggressiveness. Temozolomide (TMZ) is considered as the most widely used chemotherapy for GBM patients. Accumulating studies have proved that long non-coding RNAs (lncRNAs) participate in the pathogenesis of tumors. The aim of our study is to disclose the role of mir-99a-let-7c cluster host gene (MIR99AHG) in GBM. MIR99AHG expression was discovered to be elevated in GBM cells through quantitative real-time polymerase chain reaction (RT-qPCR) analysis. Loss-of-function experiments demonstrated that MIR99AHG silencing enhanced TMZ sensitivity of GBM both in vitro and in vivo. RNA pull down, RNA-binding protein immunoprecipitation (RIP), and luciferase reporter assays were implemented to unveil the underlying mechanism of MIR99AHG in GBM. The results of the mechanism assays implied that MIR99AHG interacted with microRNA-204-5p (miR-204-5p) and enhanced thioredoxin interacting protein (TXNIP) expression to inactivate the Nrf2/ARE signaling pathway. MIR99AHG/miR-204-5p/TXNIP regulatory axis was verified by rescue experiments in GBM. To summarize, MIR99AHG plays a promoting role in the TMZ resistance of GBM cells. The findings in this study might provide novel sight for the treatment for GBM.
胶质母细胞瘤（GBM）是成人中最常见的原发性脑肿瘤，具有高度侵袭性。替莫唑胺（TMZ）被认为是 GBM 患者最广泛使用的化疗药物。越来越多的研究证明，长非编码 RNA（lncRNA）参与肿瘤的发病机制。我们的研究旨在揭示 mir-99a-let-7c 簇宿主基因（MIR99AHG）在 GBM 中的作用。通过定量实时聚合酶链反应（RT-qPCR）分析发现，MIR99AHG 在 GBM 细胞中表达升高。功能丧失实验表明，MIR99AHG 沉默增强了 GBM 对 TMZ 的敏感性，无论是在体外还是体内。实施 RNA 下拉、RNA 结合蛋白免疫沉淀（RIP）和荧光素酶报告基因测定以揭示 MIR99AHG 在 GBM 中的潜在机制。机制测定的结果表明，MIR99AHG 与 microRNA-204-5p（miR-204-5p）相互作用并增强硫氧还蛋白相互作用蛋白（TXNIP）的表达，从而使 Nrf2/ARE 信号通路失活。在 GBM 中通过挽救实验验证了 MIR99AHG/miR-204-5p/TXNIP 调控轴。总之，MIR99AHG 在 TMZ 抵抗 GBM 细胞中发挥促进作用。本研究的结果可能为 GBM 的治疗提供新的思路。
