Abstract
Intrinsic or acquired resistance to temozolomide (TMZ) is a frequent occurrence in patients with glioblastoma (GBM). Accumulating evidence has indicated that the exosomal transfer of proteins and RNAs may confer TMZ resistance to recipient cells; however, the potential molecular mechanisms are not fully understood. Thus, the aim of the present study was to elucidate the possible role of exosomal microRNAs (miRNAs/miRs) in the acquired resistance to TMZ in GBM. A TMZ‑resistant GBM cell line (A172R) was used, and exosomes derived from A172R cells were extracted. Exosomal miR‑25‑3p was identified as a miRNA associated with TMZ resistance. The potential functions of exosomal miR‑25‑3p were evaluated by reverse transcription‑quantitative PCR, as well as cell viability, colony formation and soft agar assay, flow cytometry, western blot analysis, BrdU incorporation assay, tumor xenograft formation, luciferase reporter assay and RNA immunoprecipitation. It was found that A172R‑derived exosomes promoted the proliferation and TMZ resistance of sensitive GBM cells. Moreover, miR‑25‑3p epxression was upregulated in the exosomes of A172R cells and in serum samples of patients with GBM treated with TMZ. The depletion of exosomal miR‑25‑3p partially abrogated the effects induced by the transfer of exosomes from A172R cells. By contrast, miR‑25‑3p overexpression facilitated the proliferation and TMZ resistance of sensitive GBM cells. F‑box and WD repeat domain‑containing‑7 (FBXW7) was identified as a direct target of miR‑25‑3p. FBXW7 knockdown promoted the proliferation and TMZ resistance of GBM cells. Furthermore, the exosomal transfer of miR‑25‑3p promoted c‑Myc and cyclin E expression by downregulating FBXW7. Our results provided a novel insight into exosomal microRNAs in acquired TMZ resistance of GBM cells. Besides, exosomal miR‑25‑3p might be a potential prognostic marker for GBM patients.
Keywords:
F‑box and WD repeat domain‑containing‑7; exosome; glioblastoma; miR‑25‑3p; temozolomide.