Department of Neurosurgery, Daping Hospital and Institute Research of Surgery, Army Medical University, Chongqing, 400042, China.
Cell Death Dis. 2019 Feb 27;10(3):208. doi: 10.1038/s41419-019-1449-9.
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.
高侵袭性是胶质母细胞瘤的一个标志，并预测胶质母细胞瘤患者的预后不良。已有初步报道称，分选连接蛋白在高级别神经胶质瘤中的表达水平升高；然而，分选连接蛋白在胶质母细胞瘤进展中的潜在意义尚未阐明。在本研究中，我们研究了分选连接蛋白在胶质母细胞瘤中的致癌作用。在间充质亚型的胶质母细胞瘤和侵袭性高的胶质母细胞瘤组织和细胞系中，分选连接蛋白的水平升高。此外，分选连接蛋白水平高预示着胶质母细胞瘤患者的预后不良。分选连接蛋白敲低或用 AF38469（一种口服生物利用的分选连接蛋白抑制剂）抑制，通过抑制 EMT 样间质转化显著抑制了胶质母细胞瘤细胞的迁移和侵袭。此外，我们证明分选连接蛋白通过促进 Glycogen synthase kinase 3 beta (GSK-3β)/β-catenin/Twist 诱导的 EMT 样间质转化来促进细胞侵袭。综上所述，我们的结果表明分选连接蛋白在胶质母细胞瘤侵袭和 EMT 样间质转化中起着关键作用，表明分选连接蛋白有助于胶质母细胞瘤的进展。这些数据还突出了 AF38469 在胶质母细胞瘤中的显著抗肿瘤作用，表明 AF38469 是一种潜在的、强有力的针对分选连接蛋白过表达的人类胶质母细胞瘤的抗肿瘤药物。
