Identifying neurotrophic factor related genes at the crosstalk between glioblastoma and ischemic stroke.

BACKGROUND

Glioblastoma multiforme (GBM) and ischemic stroke (IS) are two major neurological disorders contributing substantially to global mortality and disability. GBM elevates IS risk via prothrombotic mechanisms, while IS may accelerate glioma progression through ischemia-driven neuroinflammation. Identifying shared molecular mediators is essential for understanding their bidirectional pathophysiology.

METHODS

A systems biology approach was implemented to investigate shared neurotrophic factor-related genes (NFRGs) between GBM and IS. A total of 2871 NFRGs were screened from Genecards, with Caspase-3 (CASP3) and Protein Arginine N-Methyltransferase 6 (PRMT6) identified as core regulators. Multi-omics validation included: 1) Differential expression profiling across The Cancer Genome Atlas (TCGA)-GBM and Gene Expression Omnibus (GEO) stroke datasets; 2) Prognostic stratification using Kaplan-Meier (KM) survival curves with log-rank test and Cox proportional hazards regression; 3) Immune microenvironment analysis via CIBERSORT; 4) Experimental validation in middle cerebral artery occlusion (MCAO) mice and GBM cell lines (U87MG, T98G, A172) using Real-Time Quantitative Reverse Transcription PCR (qRT-PCR), Western blot (WB), and immunofluorescence (IF).

RESULTS

CASP3 and PRMT6 were significantly upregulated in both GBM and IS (P < 0.05). KM survival analysis with log-rank test showed that high expression of CASP3 and PRMT6 was strongly associated with poorer overall survival (OS) in GBM patients (P < 0.001; Hazard Ratio (HR) = 4.375, 95% Confidence Interval (CI) = 3.336-5.738 for CASP3; HR = 4.547, 95% CI = 3.429-6.029 for PRMT6). Receiver operating characteristic (ROC) analysis confirmed robust diagnostic (Area Under the Curve (AUC) > 0.7) and prognostic efficacy for both markers. IF validated their elevated expression in ischemic brain tissues of Middle Cerebral Artery Occlusion (MCAO) mice, while qRT-PCR and WB confirmed higher expression in GBM cells versus normal glial cells. Immune infiltration analysis indicated that CASP3 and PRMT6 are associated with immunosuppressive remodeling in GBM, suggesting their role as a molecular bridge between the two diseases.

CONCLUSIONS

Our findings identify CASP3 and PRMT6 as dual molecular mediators coordinating GBM progression and post-IS pathological processes. Targeting these genes may provide novel therapeutic avenues for preventing GBM-associated IS and improving neuro-oncological outcomes.