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首页> 外文期刊>Journal of experimental & clinical cancer research : >Warburg effect-promoted exosomal circ_0072083 releasing up-regulates NANGO expression through multiple pathways and enhances temozolomide resistance in glioma
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Warburg effect-promoted exosomal circ_0072083 releasing up-regulates NANGO expression through multiple pathways and enhances temozolomide resistance in glioma

机译：Warburg效果促进外出循环循环_0072083通过多种途径释放Up-upplate Nango表达，并提高胶质瘤的替代橄榄球抗性

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Temozolomide (TMZ) resistance limits its application in glioma. Exosome can carry circular RNAs (circRNAs) to regulate drug resistance via sponging microRNAs (miRNAs). miRNAs can control mRNA expression by regulate the interaction with 3’UTR and methylation. Nanog homeobox (NANOG) is an important biomarker for TMZ resistance. Hitherto, it is unknown about the role of exosomal hsa_circ_0072083 (circ_0072083) in TMZ resistance in glioma, and whether it is associated with NANOG via regulating miRNA sponge and methylation. TMZ-resistant (n?=?36) and sensitive (n?=?33) patients were recruited. The sensitive cells and constructed resistant cells were cultured and exposed to TMZ. circ_0072083, miR-1252-5p, AlkB homolog H5 (ALKBH5) and NANOG levels were examined via quantitative reverse transcription polymerase chain reaction and western blot. The half maximal inhibitory concentration (IC50) of TMZ, cell proliferation, apoptosis, migration and invasion were analyzed via Cell Counting Kit-8, colony formation, flow cytometry, wound healing and transwell assays. The in vivo function was assessed using xenograft model. The N6-methyladenosine (m6A) level was analyzed via methylated RNA immunoprecipitation (MeRIP). Target relationship was investigated via dual-luciferase reporter assay and RNA immunoprecipitation. Warburg effect was investigated via lactate production, glucose uptake and key enzymes expression. Exosome was isolated and confirmed via transmission electron microscopy and specific protein expression. circ_0072083 expression was increased in TMZ-resistant glioma tissues and cells. circ_0072083 knockdown restrained the resistance of resistant cells via decreasing IC50 of TMZ, proliferation, migration, invasion and xenograft tumor growth and increasing apoptosis. circ_0072083 silence reduced NANOG expression via blocking ALKBH5-mediated demethylation. circ_0072083 could regulate NANOG and ALKBH5 via targeting miR-1252-5p to control TMZ resistance. Warburg effect promoted the release of exosomal circ_0072083 in resistant cells. Exosomal circ_0072083 from resistant cells increased the resistance of sensitive cells to TMZ in vitro and xenograft model. Exosomal circ_0072083 level was enhanced in resistant patients, and it had a diagnostic value and indicated a lower overall survival in glioma. Exosomal circ_0072083 promoted TMZ resistance via increasing NANOG via regulating miR-1252-5p-mediated degradation and demethylation in glioma.
机译：替莫唑胺（TMZ）电阻限制其在胶质瘤中的应用。外鼻肌可以携带圆形RNA（CircrNA）来通过海绵微小RNA（miRNA）调节耐药性。 MiRNA可以通过调节与3'UTR和甲基化的相互作用来控制mRNA表达。 Nanog Homeobox（Nanog）是一种重要的TMZ抗性的重要生物标志物。迄今为止，关于外泌体HSA_CIRC_0072083（CIRC_0072083）在胶质瘤中的TMZ抗性中的作用，以及是否通过调节miRNA海绵和甲基化与NANOG相关的作用。招募抗药性（n？= 36）和敏感（n？= 33）患者。培养敏感细胞和构造的耐药细胞并暴露于TMZ。通过定量逆转录聚合酶链反应和Western印迹检查MiR-1252-5P，MiR-1252-5P，ALKB同源物H5（ALKBH5）和纳米级水平。通过细胞计数试剂盒-8，菌落形成，流式细胞术，伤口愈合和转发测定，分析了TMZ，细胞增殖，凋亡，迁移和侵袭的半最大抑制浓度（IC50），血液形成，流式细胞术分析。使用异种移植模型评估体内功能。通过甲基化的RNA免疫沉淀（MERIP）分析N6-甲基腺苷（M6A）水平。通过双荧光素酶报告酶测定和RNA免疫沉淀研究了靶标关系。 Warburg效应通过乳酸生产，葡萄糖摄取和关键酶表达研究。通过透射电子显微镜和特异性蛋白质表达分离并确认外泌体。 Circ_0072083在TMZ抗性胶质瘤组织和细胞中增加表达。 CIRC_0072083敲低通过降低TMZ，增殖，迁移，侵袭和异种移植肿瘤生长和增加细胞凋亡，通过降低IC50抑制抗性细胞的电阻。 Circ_0072083通过阻断ALKBH5介导的去甲基化沉默降低纳米表达。 Circ_0072083可以通过靶向miR-1252-5p来调节纳米和arkbH5以控制TMZ电阻。 Warburg效果促进了外泌体循环释放的抗性细胞。来自抗性细胞的外泌体循环_0072083增加了敏感细胞对TMZ体外和异种移植模型的阻力。在抗性患者中，外泌体循环循环水平增强，它具有诊断价值，并表明胶质瘤的整体生存率较低。通过调节miR-1252-5p介导的降解和胶质瘤中的去甲基化，通过增加纳米液体促进鼻孔促进TMZ抗性。

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