Sevoflurane is associated with reduced EGFR-VEGF-AKT signaling in glioma tissues relative to propofol: a bioinformatics and clinical pilot study.

PURPOSE: This study aims to investigate the effects of sevoflurane on glioma-associated angiogenesis and to explore the potential mechanisms, providing preliminary experimental evidence for its possible association with molecular changes relevant to glioma angiogenesis. METHODS: The GSE179004 dataset was downloaded from the GEO database. This dataset consists of three glioma samples treated with sevoflurane and three untreated control samples. Differential expression analysis was performed using the limma package (|logFC|>1, P < 0.05). Candidate angiogenesis-related differentially expressed genes (ARDEGs) were identified by intersecting DEGs with angiogenesis-related genes from GeneCards, CTD, and OMIM. GO and KEGG enrichment analyses were conducted. After Benjamini-Hochberg correction, none of the 36 angiogenesis-related candidate genes reached statistical significance, reflecting the limited statistical power of the small discovery dataset. These findings should be interpreted as hypothesis-generating rather than confirmatory. A PPI network was constructed using STRING, and hub genes were identified using CytoHubba in Cytoscape. A ceRNA network was also established. Hub gene expression was validated using GEO and TCGA datasets. In the clinical study, patients received sevoflurane inhalation anesthesia throughout surgery. Human glioma tissue samples were collected intraoperatively, and expression of hub genes and VEGF-AKT pathway components was verified by qRT-PCR and Western blot. RESULTS: A total of 1,245 DEGs were identified (918 upregulated, 327 downregulated), from which 36 candidate ARDEGs were screened. Enrichment analysis showed these ARDEGs were significantly enriched in smooth muscle cell proliferation and the PI3K-AKT pathway (adj.P < 0.05, FDR<0.25). Seven hub genes were identified: EGFR, AGT, EGR1, HBEGF, ITGA2, FGFR2, and NPY. Validation in the GSE179004 dataset showed that ITGA2 and FGFR2 were significantly upregulated, while EGR1 and HBEGF were downregulated by sevoflurane (P < 0.05). TCGA analysis revealed that EGFR expression was significantly higher in glioma tissues than in normal tissues (P < 0.001) and was associated with poor prognosis (HR = 1.364, 95% CI: 1.074-1.734, P = 0.011). qRT-PCR on clinical samples demonstrated that, compared to the propofol group, the sevoflurane group had significantly increased expression of ITGA2, NPY, and FGFR2, and significantly decreased expression of EGFR, AGT, EGR1, HBEGF, and VEGFA (P < 0.05). Western blot confirmed that protein levels of EGFR, VEGF, AKT, and p-AKT were significantly reduced in the sevoflurane group (P < 0.05). No significant differences in baseline characteristics or intraoperative parameters were observed between the two groups (P >0.05). CONCLUSION: This exploratory pilot study compared sevoflurane inhalational anesthesia and propofol intravenous anesthesia in human glioma tissues. Sevoflurane reduced EGFR, VEGFA and p-AKT expression, indicating distinct regulation of the EGFR-VEGF-AKT pathway versus propofol. Notably, both agents have inherent anti-tumor and anti-angiogenic effects, so these expression changes reflect relative intergroup differences rather than absolute declines from untreated baseline. Limited by small sample size, no long-term follow-up, missing functional angiogenesis tests and no anesthesia-free controls, these findings are only hypothesis-generating and need validation in larger prospective trials with proper controls. CLINICAL TRIAL REGISTRATION: www.chictr.org.cn, identifier ChiCTR2400092575.