Abstract
Macroautophagy (autophagy) is an evolutionarily conserved process that degrades damaged proteins and organelles in a lysosome-dependent manner. It is established that autophagic activity is critical for aggressive growth of tumors and contribute to tumor survival when challenged by targeted therapies. Previous studies also indicate that the first line clinical treatments for glioblastoma (GBM), the most malignant brain cancer such as radiation therapy (RT) and temozolomide (TMZ) also induce autophagy, thereby resulting in tumor resistance to these therapies. MicroRNAs (miRNAs) are small RNAs that act as post-transcriptional regulators of gene expression and dysregulated miR expression plays an important role in cancer. The objective of this study is to whether miRNAs regulate tumorigenic behaviors and therapy response of GBM through modulating autophagic activity. Here, we determined miRNA expression profiles in patient-derived glioma stem cells (GSCs), and GBM tumors using The Cancer Genome Atlas (TCGA) data. We found that miR-93 was expressed at low levels in mesenchymal (MES) subtype tumors compared with proneural (PN) GBM. Lower levels of miR-93 expression are associated with poorer prognosis of GBM. Overexpression of miR-93 in MES GSCs reduced self-renewal and tumorigenicity in immune-compromised mice, whereas antagonizing miR-93 function in PN GSCs promoted cell growth in vitro and tumor growth in the brain of animals. By in silico prediction following experimental validation, we show that miR-93 has a suppression effect on autophagic activity in GSCs through simultaneously targeting multiple autophagy regulators, namely, BECN1, ATG5, ATG4B and SQSTM1. Moreover, RT and TMZ induce autophagy by decreasing miR-93 expression that in turn up-regulate activities of autophagy in GSCs. Inhibition of autophagy by miR-93 overexpression or suppression of autophagy enhanced therapeutic efficacy on GBM by treatments with RT and TMZ. Collectively, our findings provide novel insights for understanding miR regulation of autophagy that modulates tumorigenicity and therapy responses of GBM.