Abstract
BackgroundTemozolomide (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.MethodsTMZ-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.Resultscirc_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.ConclusionExosomal circ_0072083 promoted TMZ resistance via increasing NANOG via regulating miR-1252-5p-mediated degradation and demethylation in glioma.
Highlights
Glioma is a type of primary brain tumor with poor prognosis [1]
Exosome is a common type of extracellular vesicles with nanostructures, which can carry the cargos like noncoding RNAs to participate in the development and treatment of glioma [5, 6]
Lots of circRNAs are dysregulated, and they can interact with microRNA/mRNA axes to be involved in tumorigenesis of glioma [8]
Summary
Glioma is a type of primary brain tumor with poor prognosis [1]. Chemotherapy is one of the main therapeutic strategies, and temozolomide (TMZ), an oral alkylating agent, is widely accepted as an option for chemotherapy of glioma of all grades [2]. Exosome is a common type of extracellular vesicles with nanostructures, which can carry the cargos like noncoding RNAs to participate in the development and treatment of glioma [5, 6]. Exosomes can transfer circRNAs to control TMZ resistance in glioma, such as circRNA nuclear factor I X (circNFIX) and homeodomain interacting protein kinase 3 (circHIPK3), [9, 10].CircRNA hsa_circ_0072083 (circ_0072083) is derived from zinc finger RNA binding protein (ZFR), which may play a promoting or suppressive role in human tumors, such as gastric cancer and papillary thyroid cancer [11, 12]. 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
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