Exosomal transfer of miR-151a enhances chemosensitivity to temozolomide in drug-resistant glioblastoma.
- Resource Type
- Article
- Authors
- Zeng, Ailiang; Wei, Zhiyun; Yan, Wei; Yin, Jianxing; Huang, Xiaoxu; Zhou, Xu; Li, Rui; Shen, Feng; Wu, Weining; Wang, Xiefeng; You, Yongping
- Source
- Cancer Letters. Nov2018, Vol. 436, p10-21. 12p.
- Subject
- *DRUG resistance in cancer cells
*GLIOBLASTOMA multiforme
*TEMOZOLOMIDE
*IMMUNOPRECIPITATION
*CHEMOTHERAPY complications
- Language
- ISSN
- 0304-3835
Abstract Chemoresistance blunts the effect of Temozolomide (TMZ) in the treatment of glioblastoma multiforme (GBM). Whether exosomal transfer of miRNAs derived from TMZ-resistant GBM cells could confer TMZ resistance remains to be determined. qPCR was used to determine miR-151a expression in two TMZ-resistant GBM cell lines. The direct targets of miR-151a were identified by microarray assays, bioinformatics and further RNA chromatin immunoprecipitation (RNA-ChIP) assay. We characterized exosomes from TMZ-resistant cell lines, serum and cerebrospinal fluid (CSF) and determined the effect of exosomes from TMZ-resistant cells on recipient GBM cells. miR-151a loss drove the acquisition of TMZ resistance. Restored miR-151a expression sensitized TMZ-resistant GBM cells via inhibiting XRCC4-mediated DNA repair. TMZ-resistant GBM cells conferred TMZ chemoresistance to recipient TMZ-sensitive cells in an exosomal miR-151a loss-dependent manner. Restoration of exosomal miR-151a from donor TMZ-resistant cells abolished the chemoresistance dissemination that was directed by donor TMZ-resistant cells. CSF-derived exosomes contained miRNA signatures reflective of the underlying chemoresistant status of GBMs in terms of miR-151a expression levels. Exosomal miR-151a is not only essentially a less-invasive ‘liquid biopsy’ that might predict chemotherapy response, but also represents a promising therapeutic target for therapy-refractory GBMs. Highlights • Low miR-151a levels of GBM patients correlate with poor response to TMZ therapy. • Overexpression of miR-151a restores TMZ response of resistant GBM cells in vivo. • miR-151a could be packaged into exosomes and disseminate TMZ chemosensitivity. • miR-151a is a clinical indicator and therapeutic target for GBM TMZ resistance. [ABSTRACT FROM AUTHOR]