Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Department of Operation, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Brain Res. 2021 Aug 15;1765:147500. doi: 10.1016/j.brainres.2021.147500. Epub 2021 Apr 22.
Spindle and kinetochore-related complex subunit 3 (SKA3) is a key modulator of the progression of multiple tumor types. However, the involvement of SKA3 in glioblastoma (GBM) has not been well studied. The current study aimed to explore the role of SKA3 expression and the potential function of the protein in GBM. Our data showed that SKA3 expression was significantly up-regulated in GBM. Functional assays demonstrated that the knockdown of SKA3 impeded the proliferation, colony formation and invasion of GBM cells, while SKA3 overexpression produced the opposite effects. Further investigation revealed that SKA3 overexpression enhanced the activation of Wnt/β-catenin signaling, which was associated with the enhanced phosphorylation of Akt and glycogen synthase kinase-3β (GSK-3β). Notably, the inhibition of Akt markedly abrogated the SKA3 overexpression-induced promotion of Wnt/β-catenin signaling in GBM cells. Further, the inhibition of Wnt/β-catenin signaling markedly abrogated the SKA3 overexpression-induced promotion of tumor growth. In addition, the knockdown of SKA3 significantly retarded tumor formation and GBM progression in vivo. In summary, these data demonstrate that SKA3 exerts promotes tumor growth in GBM by enhancing the activation of Wnt/β-catenin signaling via modulation of the Akt/GSK-3β axis. This work highlights the pivotal role of SKA3/Akt/GSK-3β/Wnt/β-catenin signaling in the progression of GBM and suggests that SKA3 is an attractive therapeutic target with potential to be used to treat GBM.
纺锤体和着丝粒相关复合物亚基 3（SKA3）是多种肿瘤进展的关键调节剂。然而，SKA3 在神经胶质瘤（GBM）中的作用尚未得到充分研究。本研究旨在探讨 SKA3 表达与 SKA3 蛋白在 GBM 中的潜在功能。我们的数据显示，SKA3 在 GBM 中表达显著上调。功能测定表明，SKA3 的敲低抑制了 GBM 细胞的增殖、集落形成和侵袭，而 SKA3 的过表达则产生了相反的效果。进一步研究表明，SKA3 的过表达增强了 Wnt/β-catenin 信号的激活，这与 Akt 和糖原合成酶激酶-3β（GSK-3β）的磷酸化增强有关。值得注意的是，Akt 的抑制显著阻断了 SKA3 过表达诱导的 GBM 细胞中 Wnt/β-catenin 信号的激活。此外，Wnt/β-catenin 信号的抑制显著阻断了 SKA3 过表达诱导的肿瘤生长促进作用。此外，SKA3 的敲低显著减缓了体内肿瘤形成和 GBM 进展。综上所述，这些数据表明，SKA3 通过调节 Akt/GSK-3β 轴增强 Wnt/β-catenin 信号的激活，从而促进 GBM 中的肿瘤生长。这项工作强调了 SKA3/Akt/GSK-3β/Wnt/β-catenin 信号在 GBM 进展中的关键作用，并表明 SKA3 是一个有吸引力的治疗靶点，具有治疗 GBM 的潜力。
