MiR-4524b-5p-targeting ALDH1A3 attenuates the proliferation and radioresistance of glioblastoma via PI3K/AKT/mTOR signaling

Abstract

Increasing evidence has revealed a strong connection between the aldehyde dehydrogenase family member ALDH1A3 and tumorigenesis, therapy resistance, and prognosis in diverse types of cancer. However, the specific miRNA involved in the pathways that regulate ALDH1A3-mediated glioblastoma (GBM) radioresistance remains to be elucidated. In this study, we demonstrated a high expression of ALDH1A3 in GBM cells, which plays a critical role in their proliferation and radioresistance. We also identified miR-4524b-5p, which is downregulated in GBM, as the ALDH1A3 upstream regulator. Overexpression of miR-4524b-5p reduced proliferation and radioresistance in GBM cells. Moreover, silencing ALDH1A3 reduced PI3K/AKT/mTOR signaling and glycolytic activity in GBM cells, whereas inhibiting mTOR reversed the radioresistance effects of ALDH1A3 on these cells. In vivo experiments have evidenced that ALDH1A3 silencing and miR-4524b-5p overexpression significantly reduced tumor growth and GBM cells radioresistance. In summary, targeting the miR-4524b-5p and ALDH1A3 axis is a promising therapeutic strategy for treating GBM.