Identification of RASL11A as a gene conferring radiosensitivity in glioblastoma.

PURPOSE

Radioresistance poses a significant challenge in the treatment of glioblastoma (GBM). This study investigates the role of Ras-like protein family member 11 A (RASL11A), which is upregulated in GBM cells following X-ray irradiation (IR), in modulating radiosensitivity.

MATERIALS AND METHODS

The mRNA-seq data comprising 699 human glioma samples of different grades from The Cancer Genome Atlas (TCGA) was analyzed to explore the relationship between RASL11A expression and clinical outcomes in glioma patients. RASL11A was overexpressed in U251 cells and knocked out in U87 cells, with subsequent assays to evaluate its impacts on radiosensitivity in vitro and in vivo. Transcriptome sequencing was performed and p-STAT3 levels were assessed in GBM cells following IR treatment.

RESULTS

Analysis of mRNA-seq data from 699 glioma samples in The Cancer Genome Atlas (TCGA) revealed that higher RASL11A expression correlates with poor clinical outcomes. In vitro experiments demonstrated that RASL11A overexpression in U251 cells or RASL11A knockout in U87 cells significantly affected radiosensitivity. Cells with higher RASL11A levels exhibited increased clonogenic survival, reduced G2/M arrest, decreased γ-H2AX levels, and lower apoptosis rates after X-ray IR. In vivo studies corroborated these findings, showing larger tumor volumes and weights, along with decreased levels of C-Caspase 3 and increased Ki67 expression in RASL11A-overexpressing U251 tumors with IR treatment. Higher RASL11A altered the transcriptome landscape and promoted STAT3 phosphorylation in GBM cells following IR exposure.

CONCLUSIONS

RASL11A appears to reduce radiosensitivity by enhancing STAT3 phosphorylation in GBM cells, highlighting its potential as a therapeutic target for optimizing radiotherapy efficacy.