EIF4A3-induced circular RNA ASAP1 promotes tumorigenesis and temozolomide resistance of glioblastoma via NRAS/MEK1/ERK1-2 signaling.
EIF4A3-induced circular RNA ASAP1 promotes tumorigenesis and temozolomide resistance of glioblastoma via NRAS/MEK1/ERK1-2 signaling.
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EIF4A3诱导的环状RNA ASAP1(circASAP1)通过NRAS/MEK1/ERK1/2信号促进胶质母细胞瘤的肿瘤发生和替莫唑胺耐药
DOI：
10.1093/neuonc/noaa214
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发表时间：
2021-04-12
期刊：
影响因子：
15.9
通讯作者：
You Y
中科院分区：
文献类型：
--
作者：
Wei Y;Lu C;Zhou P;Zhao L;Lyu X;Yin J;Shi Z;You Y
获得性耐药是胶质母细胞瘤（GBM）临床治疗的主要挑战。已经证实环状RNA在肿瘤化学抗性中起作用。然而，其潜在机制仍不清楚。本研究旨在阐明具有Src同源3结构域、锚蛋白重复序列和Pleckstrin同源结构域1的环状RNA ADP核糖基化因子GT3激活蛋白（circASAP 1）在GBM对替莫唑胺（TMZ）耐药中的潜在作用及其分子机制。我们通过RNA测序分析了复发性GBM组织相对于原发性GBM的circRNA改变。实时定量逆转录PCR证实circASAP 1在组织和细胞中表达。使用敲低和过表达质粒来评估circASAP 1对GBM细胞增殖和TMZ诱导的凋亡的影响。在机制上，进行荧光原位杂交、双荧光素酶报告基因和RNA免疫沉淀测定以确认circASAP 1/miR-502- 5 p/神经母细胞瘤Ras（NRAS）的调控网络。颅内肿瘤模型被用来验证我们的研究结果在体内。CircASAP 1表达在复发性GBM组织和TMZ耐药细胞系中显著上调。CircASAP 1过表达增强GBM细胞增殖和TMZ抗性，这可以通过circASAP 1敲低来降低。进一步的实验表明，circASAP 1通过海绵状的miR-502- 5 p增加NRAS的表达。此外，circASAP 1耗竭有效地恢复了TMZ耐药异种移植物对体内TMZ治疗的敏感性。我们的数据表明，circASAP 1发挥调节功能，在GBM和竞争内源性（ce）RNA介导的microRNA螯合可能是一个潜在的治疗策略GBM治疗。
Acquired chemoresistance is a major challenge in the clinical treatment of glioblastoma (GBM). Circular RNAs have been verified to play a role in tumor chemoresistance. However, the underlying mechanisms remain unclear. The aim of this study was to elucidate the potential role and molecular mechanism of circular (circ)RNA ADP-ribosylation factor GTPase activating proteins with Src homology 3 domain, ankyrin repeat and Pleckstrin homology domain 1 (circASAP1) in temozolomide (TMZ) resistance of GBM. We analyzed circRNA alterations in recurrent GBM tissues relative to primary GBM through RNA sequencing. Real-time quantitative reverse transcription PCR verified the expression of circASAP1 in tissues and cells. Knockdown and overexpressed plasmids were used to evaluate the effect of circASAP1 on GBM cell proliferation and TMZ-induced apoptosis. Mechanistically, fluorescent in situ hybridization, dual-luciferase reporter, and RNA immunoprecipitation assays were performed to confirm the regulatory network of circASAP1/miR-502-5p/neuroblastoma Ras (NRAS). An intracranial tumor model was used to verify our findings in vivo. CircASAP1 expression was significantly upregulated in recurrent GBM tissues and TMZ-resistant cell lines. CircASAP1 overexpression enhanced GBM cell proliferation and TMZ resistance, which could be reduced by circASAP1 knockdown. Further experiments revealed that circASAP1 increased the expression of NRAS via sponging miR-502-5p. Moreover, circASAP1 depletion effectively restored the sensitivity of TMZ-resistant xenografts to TMZ treatment in vivo. Our data demonstrate that circASAP1 exerts regulatory functions in GBM and that competing endogenous (ce)RNA-mediated microRNA sequestration might be a potential therapeutic strategy for GBM treatment.
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