Abstract
BackgroundAcquired drug resistance is a constraining factor in clinical treatment of glioblastoma (GBM). However, the mechanisms of chemoresponsive tumors acquire therapeutic resistance remain poorly understood. Here, we aim to investigate whether temozolomide (TMZ) resistance of chemoresponsive GBM was enhanced by long non-coding RNA SBF2 antisense RNA 1 (lncRNA SBF2-AS1) enriched exosomes.MethodLncSBF2-AS1 level in TMZ-resistance or TMZ-sensitive GBM tissues and cells were analyzed by qRT-PCR and FISH assays. A series of in vitro assay and xenograft tumor models were performed to observe the effect of lncSBF2-AS1 on TMZ-resistance in GBM. CHIP assay were used to investigate the correlation of SBF2-AS1 and transcription factor zinc finger E-box binding homeobox 1 (ZEB1). Dual-luciferase reporter, RNA immunoprecipitation (RIP), immunofluorescence and western blotting were performed to verify the relation between lncSBF2-AS1, miR-151a-3p and XRCC4. Comet assay and immunoblotting were performed to expound the effect of lncSBF2-AS1 on DNA double-stand break (DSB) repair. A series of in vitro assay and intracranial xenografts tumor model were used to determined the function of exosomal lncSBF2-AS1.ResultIt was found that SBF2-AS1 was upregulated in TMZ-resistant GBM cells and tissues, and overexpression of SBF2-AS1 led to the promotion of TMZ resistance, whereas its inhibition sensitized resistant GBM cells to TMZ. Transcription factor ZEB1 was found to directly bind to the SBF2-AS1 promoter region to regulate SBF2-AS1 level and affected TMZ resistance in GBM cells. SBF2-AS1 functions as a ceRNA for miR-151a-3p, leading to the disinhibition of its endogenous target, X-ray repair cross complementing 4 (XRCC4), which enhances DSB repair in GBM cells. Exosomes selected from temozolomide-resistant GBM cells had high levels of SBF2-AS1 and spread TMZ resistance to chemoresponsive GBM cells. Clinically, high levels of lncSBF2-AS1 in serum exosomes were associated with poor response to TMZ treatment in GBM patients.ConclusionWe can conclude that GBM cells remodel the tumor microenvironment to promote tumor chemotherapy-resistance by secreting the oncogenic lncSBF2-AS1-enriched exosomes. Thus, exosomal lncSBF2-AS1 in human serum may serve as a possible diagnostic marker for therapy-refractory GBM.
Highlights
Malignant glioma is the most common primary malignant tumor in the brain as well as being the most lethal in adults
We can conclude that GBM cells remodel the tumor microenvironment to promote tumor chemotherapy-resistance by secreting the oncogenic lncSBF2-AS1-enriched exosomes
Purified exosomes were authenticated by transmission electron microscopy (TEM) analysis and Western blotting analysis (Fig. 9a and b). quantitative reverse transcription (qRT)-PCR assay was performed, and we found that exosomal lncSBF2-AS1 was enriched in the serum of recurrent GBM patients instead of primary GBM patients (Fig. 9c)
Summary
Malignant glioma is the most common primary malignant tumor in the brain as well as being the most lethal in adults. Resistance to TMZ and subsequent tumor recurrence has become difficult and critical problems in the clinical treatment of GBM. Exosomes secreted by tumor cells serve as a key mediator of tumor communication between tumor cells or with other cells in the microenvironment It has emerged as a new model for research into tumor resistance and become a new hotspot in the study of drug resistance in tumor biology. Acquired drug resistance is a constraining factor in clinical treatment of glioblastoma (GBM). The mechanisms of chemoresponsive tumors acquire therapeutic resistance remain poorly understood. We aim to investigate whether temozolomide (TMZ) resistance of chemoresponsive GBM was enhanced by long noncoding RNA SBF2 antisense RNA 1 (lncRNA SBF2-AS1) enriched exosomes
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