Apolipoprotein E (APOE) Promotes Cell Proliferation and Invasion in Glioma via the PI3K/AKT Signaling Pathway

Mengdi Xia,1 Ke Chen,1 Weiwei Chen,2 Zhenhua Ren,1 Xiaohui Li1 1Department of Anatomy, School of Basic Medicine, Anhui Medical University, Hefei, Anhui, 230032, People’s Republic of China; 2Department of Neurosurgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of ChinaCorrespondence: Xiaohui Li, Email [email protected] Zhenhua Ren, Email [email protected]: Glioma presents significant therapeutic challenges due to its marked heterogeneity and resistance to conventional treatments. Apolipoprotein E (APOE), a glycoprotein involved in lipid metabolism, has been reported to be dysregulated in glioma; however, its functional role in glioma progression remains poorly understood.Methods: APOE expression in glioma was analyzed using publicly available transcriptomic datasets from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA). Functional studies were performed in U251MG and U87MG glioma cells with APOE overexpression or knockout. Cell proliferation, migration, and invasion were evaluated using CCK-8, Edu, Transwell, and wound-healing assay. Mechanistic analyses included RNA sequencing, immunofluorescence, nucleocytoplasmic fractionation, Western blotting and immunoprecipitation. A nude mouse xenograft model was used to assess tumor growth in vivo.Results: APOE expression was elevated in glioma datasets. Functional assays demonstrated that APOE promotes glioma cell proliferation, migration, and invasion. Notably, APOE was detected in the nucleus, where it exhibited transcriptional regulatory activity. Mechanistically, APOE overexpression significantly activated the PI3K/AKT signaling pathway, and this effect was effectively reversed by the PI3K inhibitor LY294002. Consistently, APOE overexpression enhanced tumor growth in vivo.Conclusion: These findings indicate that APOE promotes glioma progression through nuclear activity and activation of the PI3K/AKT signaling pathway, highlighting APOE-related signaling as a potential therapeutic target in glioma.Keywords: glioma, APOE, PI3K/AKT signaling pathway, tumor progression, nuclear translocation