Identification of a miRNA multi-targeting therapeutic strategy in glioblastoma

Glioblastoma (GBM) is a deadly and the most common primary brain tumor in adults. Due to their regulation of a high number ofmRNA transcripts, microRNAs (miRNAs) are key molecules in the control of biological processes and are thereby promisingtherapeutic targets for GBM patients. In this regard, we recently reported miRNAs as strong modulators of GBM aggressiveness.Here, using an integrative and comprehensive analysis of the TCGA database and the transcriptome of GBM biopsies, we identifiedthree critical and clinically relevant miRNAs for GBM, miR-17-3p, miR-222, and miR-340. In addition, we showed that thecombinatorial modulation of three of these miRNAs efficiently inhibited several biological processes in patient-derived GBM cells ofall these three GBM subtypes (Mesenchymal, Proneural, Classical), induced cell death, and delayed tumor growth in a mouse tumormodel. Finally, in a doxycycline-inducible model, we observed a significant inhibition of GBM stem cell viability and a significantdelay of orthotopic tumor growth. Collectively, our results reveal, for the first time, the potential of miR-17-3p, miR-222 and miR-340multi-targeting as a promising therapeutic strategy for GBM patients.Cell Death and Disease (2023) 14:630 ; https://doi.org/10.1038/s41419-023-06117-z Overall design: In this study, by harnessing the wealth of public data stored in the Cancer Genome Atlas Research Network (TCGA) database, we identified miR-17-3p, miR-222, and miR-340 as three clinically relevant miRNAs that can be used for a GBM multitargeting therapeutic strategy. Thus, to get some insight into the potential regulated genes, we performed RNASeq on GBM cell line transfected with the identified miRNAs.