MiR-22-3p shapes glioblastoma radiation resistance and downregulates the DNA demethylase tumor suppressor TET1

Abstract Glioblastoma (GB) is an aggressive brain tumor characterized by marked radioresistance and poor clinical outcomes. MicroRNAs (miRNAs) are key post-transcriptional regulators implicated in tumor progression and therapeutic response. Here, we investigated radiation-induced miRNA modulation in patient-derived cancer stem-like cell (CSLC) neurospheres exposed to internal radionuclide therapy using rhenium-188-loaded lipid nanocapsules ( 188 Re-LNC). MiRNA profiling following 188 Re-LNC treatment identified miR-22-3p, miR-197-3p, and miR-574-3p as potential candidates for functional characterization. Lentiviral-mediated overexpression in U87MG cells revealed distinct phenotypes, with miR-22-3p promoting proliferation and clonogenic survival, whereas miR-197-3p primarily enhanced migratory capacity while miR-574-3p had little effect on either phenotype. In an orthotopic murine xenograft model, miR-22-3p and miR-197-3p overexpression accelerated tumor progression and was associated with reduced survival. Notably, upon 188 Re-LNC treatment, miR-22-3p-expressing tumors exhibited pronounced radioresistance, with a complete absence of long-term survivors, while miR-197-3p-expressing tumors remained responsive to therapy. AntagomiR-mediated inhibition of miR-22-3p restored radiosensitivity in vitro and was accompanied by upregulation of the DNA demethylase TET1 that is identified here as a candidate functional target of miR-22-3p. Together, these findings identify miR-22-3p as a critical mediator of GB radioresistance and miR-197-3p as a driver of invasion, supporting their relevance as therapeutic targets and predictive biomarkers to improve radiotherapy stratification and efficacy in GB.