Abstract
High aggressiveness is a hallmark of glioblastoma and predicts poor prognosis of patients with glioblastoma. The expression level of sortilin has been preliminarily reported to be elevated in high-grade glioma; however, the potential significance of sortilin in glioblastoma progression has not been elucidated. In this study, we investigated the oncogenic effect of sortilin in glioblastoma. Increased levels of sortilin were noted in the mesenchymal subtype of glioblastoma and highly aggressive subtypes of glioblastoma tissues and cell lines. In addition, high levels of sortilin predicted poor prognoses in patients with glioblastoma. Sortilin knockdown or inhibition with AF38469 (an orally bioavailable inhibitor of sortilin) significantly suppressed migration and invasion by inhibiting EMT-like mesenchymal transition in glioblastoma cells. Furthermore, we proved that sortilin promoted cell invasion mainly via Glycogen synthase kinase 3 beta (GSK-3β)/β-catenin/Twist-induced EMT-like mesenchymal transition in glioblastoma. Taken together, our results demonstrate a critical role of sortilin in glioblastoma invasion and EMT-like mesenchymal transition, indicating that sortilin contributes to glioblastoma progression. These data also highlight the dramatic antitumor effects of AF38469 in glioblastoma, suggesting that AF38469 is a potentially powerful antitumor agent for sortilin-overexpressing human glioblastoma.
Highlights
Human glioblastoma (GBM) is the most common and aggressive form of malignant primary tumor in the central nervous system (CNS)[1]
To preliminarily investigate the relationship between the expression levels of sortilin and the prognosis of glioma patients, we employed the Gravedeel dataset from R2: Genomics Analysis and Visualization Platform (RGAVP), which includes 273 glioma cases with different histological grades
Due to the prognosis of GBM being significantly worse than lowgrade glioma, the magnitude of difference in Gravedeel dataset was greater than the GBM-TCGA dataset
Summary
Human glioblastoma (GBM) is the most common and aggressive form of malignant primary tumor in the central nervous system (CNS)[1]. Tumor invasion is a hot topic in the field, the mechanisms underlying GBM invasion are still not entirely understood. A recent report has confirmed that the mesenchymal subtype is closely related to the high invasive capacity of GBM6. WNT/β-catenin contributes to mesenchymal transition; WNT and β-catenin are expressed at high levels and are correlated with a significantly short survival time in patients with GBM7,8. WNT/β-catenin is activated in GBM and contributes to tumor invasion by triggering the expression of EMT activators such as Twist, Snail, and ZEB19. Accumulating evidence indicates that Twist, a downstream activator of WNT/β-catenin, is highly expressed in GBM and promotes cell invasion by regulating the expression of mesenchymal target genes[10,11]
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