Activation of SV2B Inhibits Matrix-Stiffness-Induced Tumorigenesis and EMT in Glioma via FAK/PI3K/AKT Signaling Pathway

INTRODUCTION: Growing evidence suggests that increased matrix stiffness can significantly enhance the malignant characteristics of glioma cells. However, the mechanisms by which increased matrix stiffness regulates the tumorigenesis of glioma cells remain largely unknown. A growing number of studies show that carcinogenesis in various human cancers is linked to cell membrane glycoproteins and their corresponding receptors. Among these, synaptic vesicle glycoprotein 2 isoforms B (SV2B) has emerged as a transmembrane glycoprotein with significant functional implications. However, whether SV2B is involved in matrix-stiffness-mediated glioma tumorigenesis and its related mechanisms remains to be elucidated. METHODS: In this study, we aimed to investigate whether SV2B mediates the effects of matrix stiffness on the focal adhesion kinase (FAK)/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway. To examine the expression of SV2B in patients with glioma, we analyzed data from bioinformatics databases. Furthermore, we assessed SV2B variation in glioma and its impact on overall survival. In vitro experiments included Western blot and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analyses to determine protein and messenger RNA (mRNA) expression in glioma cell lines. Cell viability and DNA replication capacity were evaluated using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), and colony formation assays. Migration ability was assessed through Transwell and wound healing assays. Flow cytometry was employed to analyze apoptotic rates in glioma cells. Additionally, an orthotopic tumorigenesis model was established to investigate the in vivo effects of SV2B. RESULTS: Our results demonstrated low expression of SV2B in glioma tissues. Overexpression of SV2B was found to inhibit proliferation and migration and induce apoptosis of glioblastoma cells, while knockdown of SV2B promoted these processes. Furthermore, we observed that SV2B overexpression suppressed the epithelial-mesenchymal transition (EMT) process and inhibited the activation of the FAK/PI3K/AKT signaling pathway in glioma cells, with similar effects observed in vivo. Finally, we demonstrated that increased matrix stiffness can promote glioma tumor growth through FAK/PI3K/AKT pathway, while overexpression of SV2B can inhibit this effect. CONCLUSIONS: Our study provides insights into the functional role of SV2B in matrix-stiffness-driven glioma progression, elucidating its molecular mechanisms and highlighting its potential as a therapeutic target.