Department of Neurosurgery, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
Cell Oncol (Dordr). 2019 Dec;42(6):801-813. doi: 10.1007/s13402-019-00463-x. Epub 2019 Jul 10.
Glioblastoma (GBM) stem cells (GSCs) have been found to be the main cause of malignant GBM progression. It has also been found that Quaking homolog (QKI) plays a predominant role in driving GBM development. Here, we aimed to asses the role of QKI in maintaining GSC stemness and inducing the invasiveness of GBM cells.
Public databases were used to assess the expression of QKI and its correlation with stemness markers in primary GBMs. The CRISPR-Cas9 technology was used to generate QKI knockout GBM cells, and RNA immunoprecipitation was used to assess QKI-GLI1 protein-mRNA interactions. In addition, in vitro and in vivo GBM cell proliferation, migration, xenografting and neurosphere formation assays were performed.
Using public GBM databases, QKI was identified as a potential GSC regulator. We found that QKI could inhibit stem-like cell (SLC) stemness and prolong the survival of xenografted mice. Mechanistically, we found that QKI knockout increased the GLI Family Zinc Finger 1 (GLI1) mRNA level, which is essential for maintaining the self-renewal ability of GSCs. In addition, we found that QKI knockout activated the Hedgehog signaling pathway via Tra-2 and GLI response element (TGE)-specific GLI1 mRNA disruption.
Our data indicate that upregulation of GLI1 induced by QKI deficiency maintains GSC stemness and enhances the invasiveness of GBM cells, thereby hinting at new options for the treatment of GBM.
胶质母细胞瘤（GBM）干细胞（GSCs）已被发现是恶性 GBM 进展的主要原因。还发现 Quaking 同源物（QKI）在驱动 GBM 发展中起主要作用。在这里，我们旨在评估 QKI 在维持 GSC 干性和诱导 GBM 细胞侵袭性方面的作用。
使用公共数据库评估 QKI 的表达及其与原发性 GBM 中干性标志物的相关性。使用 CRISPR-Cas9 技术生成 QKI 敲除 GBM 细胞，并使用 RNA 免疫沉淀评估 QKI-GLI1 蛋白-mRNA 相互作用。此外，还进行了体外和体内 GBM 细胞增殖、迁移、异种移植和神经球形成测定。
使用公共 GBM 数据库，鉴定出 QKI 是一种潜在的 GSC 调节剂。我们发现 QKI 可以抑制类干细胞（SLC）干性并延长异种移植小鼠的存活时间。在机制上，我们发现 QKI 敲除增加了 GLI 家族锌指蛋白 1（GLI1）mRNA 水平，这对于维持 GSCs 的自我更新能力至关重要。此外，我们发现 QKI 敲除通过 Tra-2 和 GLI 反应元件（TGE）特异性 GLI1 mRNA 破坏激活了 Hedgehog 信号通路。
我们的数据表明，QKI 缺陷诱导的 GLI1 上调维持了 GSC 干性并增强了 GBM 细胞的侵袭性，从而为 GBM 的治疗提供了新的选择。
