Tumor-Suppressive microRNA Therapy Inhibits Growth of Glioblastoma Multiforme Xenografts

Glioblastoma multiforme (GBM) is defined by rapid progression, high invasiveness, and a poor prognosis, with a median survival of only ≅13 months despite current treatments. Its marked genetic heterogeneity, high mutational burden, and cancer stem cell population make GBM exceptionally difficult to treat, highlighting the urgent need for more effective, multitargeted therapies. Non-coding RNAs, particularly tumor suppressor microRNAs (miRNAs), have gained attention for suppressing key oncogenic processes that drive tumorigenesis, metastasis, and drug resistance, positioning them as promising tools for targeting multiple oncogenic pathways. We recently found that FOXM1/AXL-eEF2K collaboratively drive GBM cell proliferation, survival, and invasion through the formation of a signaling hub complex. In this study, we employed miRNA prediction algorithms to identify a specific miRNA, in vitro functional assays and in vivo GBM flank model to target GBM tumorigenesis by distrupting the FOXM1/AXL-eEF2K signaling hub. Our results indicated that FOXM1, AXL, and eEF2K are overexpressed in GBM patient tumors. To target the FOXM1/AXL-eEF2K signaling hub, we identified miR-449b-5p, miR-329-3p, and miR-518c as potential co-inhibitors of FOXM1/AXL-eEF2K and suppressors of cell proliferation, migration-invasion, and spheroid formation. Furthermore, the combination of miR-449b-5p, miR-329-3p, and miR-518c treatments with temozolomide led to synergistic enhancements in cell proliferation suppression and the induction of apoptosis and ferroptosis. More importantly, in vivo miR-329-3p treatment led to remarkable suppression of GBM tumor xenografts. These findings indicate that miR-329-3p-based tumor suppressor therapy may offer a multitargeted approach for GBM treatment.