Unraveling the pro-oncogenic role of GLIPR2: Its molecular basis in glioma malignancy

Adult diffuse gliomas remain challenging to treat because of their infiltrative growth and resistance to multimodal therapy. Although GLIPR2 has been implicated in autophagy regulation and tumor-related processes, its role in glioma remains unclear. In this study, transcriptomic and clinical data from TCGA, CGGA, and GTEx were integrated with western blotting and immunohistochemical validation in human glioma specimens. Prognostic significance was evaluated using Kaplan-Meier and ROC analyses. Functional effects of GLIPR2 knockdown were examined in U138 and U251 glioma cells through assays of proliferation, migration, invasion, apoptosis, DNA damage, and clonogenic survival. KEGG enrichment analysis and western blotting were used to investigate associated signaling pathways. GLIPR2 expression was significantly elevated in gliomas, predominantly localized in the cytoplasm, and positively correlated with tumor grade. High GLIPR2 expression was associated with unfavorable overall survival and demonstrated predictive value for 1-, 3-, and 5-year survival. Silencing GLIPR2 inhibited glioma cell proliferation, migration, and invasion while promoting apoptosis. Moreover, GLIPR2 knockdown enhanced irradiation-induced γ-H2AX accumulation and reduced post-irradiation clonogenic survival, indicating impaired resolution of radiation-induced DNA damage and increased radiosensitivity. Mechanistically, GLIPR2 depletion was accompanied by reduced PI3K/AKT pathway activity and lower p-GSK-3β and MMP9 expression, without altering total GSK-3β levels. These findings identify GLIPR2 as a glioma-associated biomarker linked to malignant progression, unfavorable prognosis, and radioresistance and nominate it as an investigational molecular vulnerability for further validation.