MicroRNA miR-22-3p drives radiation resistance in glioblastoma by suppressing TET1

Glioblastoma remains one of the most aggressive brain tumors, marked by pronounced radioresistance and poor clinical outcomes. A new open-access study published in the Journal of Experimental & Clinical Cancer Research reports that a small regulatory RNA, miR-22-3p, promotes radiation resistance in glioblastoma models and appears to act in part by downregulating TET1, a DNA demethylase with tumor-suppressive properties.

The research team investigated how microRNAs change in patient-derived cancer stem-like cell neurospheres exposed to internal radionuclide therapy using lipid nanocapsules loaded with rhenium-188. MiRNA profiling after this treatment highlighted three candidates for functional analysis: miR-22-3p, miR-197-3p, and miR-574-3p.

To test what each candidate does, the researchers used lentiviral-mediated overexpression in U87MG glioblastoma cells. The three microRNAs produced distinct phenotypes. MiR-22-3p promoted cell proliferation and clonogenic survival, the ability of individual cells to form colonies after stress. MiR-197-3p primarily enhanced migratory capacity, while miR-574-3p had little effect on either proliferation or migration.

The team then moved to an orthotopic murine xenograft model, in which tumor cells are implanted in the brain. Overexpression of either miR-22-3p or miR-197-3p accelerated tumor progression and was associated with reduced survival in the animals, indicating that both microRNAs can act as drivers of aggressive disease in vivo.

The most striking result emerged when the tumors were treated with the rhenium-188-loaded nanocapsules. Tumors expressing miR-22-3p showed pronounced radioresistance, with a complete absence of long-term survivors in that group. In contrast, tumors expressing miR-197-3p remained responsive to the therapy, despite their invasive phenotype. This dissociation suggests the two microRNAs shape therapeutic response through different mechanisms.

AntagomiR-mediated inhibition of miR-22-3p restored radiosensitivity in vitro. Notably, this inhibition was accompanied by upregulation of TET1, a DNA demethylase, which the study identifies as a candidate functional target of miR-22-3p.

The authors propose that the miR-22-3p–TET1 axis contributes to the radioresistant state of glioblastoma cells, although the findings are based on cell and xenograft models rather than patient trials.

Overall, the study positions miR-22-3p as a critical mediator of glioblastoma radioresistance and miR-197-3p as a driver of invasion. The authors argue that both microRNAs merit attention as therapeutic targets and as potential predictive biomarkers that could improve stratification of patients and the efficacy of radiotherapy in glioblastoma. As the article is being shared early as a peer-reviewed, accepted manuscript with a permanent DOI, some details may still be refined in the final version of record.

Subject of Research: The role of the microRNA miR-22-3p in glioblastoma radiation resistance and its regulation of the TET1 tumor suppressor

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

Article References: Loussouarn, C., Roncali, L., Etcheverry, A., Roy, C., Clavreul, A., Lacoeuille, F., Rousseau, A., Lemée, J. M., Menei, P., Karayan-Tapon, L., Mosser, J., Hindré, F., Baril, P., & Garcion, E. (2026). MiR-22-3p shapes glioblastoma radiation resistance and downregulates the DNA demethylase tumor suppressor TET1. Journal of Experimental & Clinical Cancer Research. https://doi.org/10.1186/s13046-026-03841-0

Image Credits: AI Generated

DOI: 10.1186/s13046-026-03841-0

Keywords: glioblastoma, miR-22-3p, TET1, radioresistance, microRNA, rhenium-188, lipid nanocapsules, antagomiR, U87MG, xenograft model, DNA demethylation, cancer stem-like cells