α-Synuclein suppresses glioma progression through the CDH13-JNK/c-Jun pathway.

PURPOSE: Gliomas are highly invasive primary brain tumors, and additional biomarkers are needed to improve prognostic stratification and clarify the mechanisms underlying tumor invasion. Although α-synuclein (α-syn), encoded by SNCA, is a central protein in neurodegenerative disease, its role in glioma remains poorly defined. METHODS: SNCA/α-syn expression was evaluated in glioma specimens from Beijing Tiantan Hospital and in the Chinese Glioma Genome Atlas and The Cancer Genome Atlas cohorts. Associations with clinicopathological characteristics, molecular features, and overall survival were analyzed. Gain- and loss-of-function experiments were performed in U87 cells and patient-derived glioma stem-like cells (GSLCs), followed by proliferation, migration, invasion, and pathway-rescue assays. An orthotopic xenograft model was used to assess tumor growth and survival in vivo. RESULTS: SNCA/α-syn expression was lower in high-grade gliomas and was associated with favorable molecular features and prolonged survival. α-Syn overexpression inhibited glioma cell proliferation, migration, and invasion, whereas α-syn knockdown promoted proliferation and invasion in GSLCs. Mechanistically, α-syn increased CDH13 expression, activated JNK/c-Jun signaling, and reduced MMP3 and MMP9 expression. CDH13 knockdown or JNK inhibition attenuated these effects and restored glioma cell migration and invasion. In vivo, α-syn overexpression suppressed orthotopic tumor growth and prolonged survival. CONCLUSION: High SNCA/α-syn expression is associated with favorable prognosis, whereas α-syn functions as a suppressor of glioma progression, at least partly through the CDH13-JNK/c-Jun axis.