Bo Han1,2,3, Ruijia Wang1,3, Yongjie Chen1,3, Xiangqi Meng1,3, Pengfei Wu1,3, Ziwei Li1,3, Chunbin Duan1,3, Qingbin Li1,3, Yang Li1,3, Shihong Zhao1,3, Chuanlu Jiang4,5, Jinquan Cai6,7. 1. Department of Neurosurgery, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China. 2. Beijing Neurosurgical Institute, Capital Medical University, Beijing, China. 3. Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin, 150086, China. 4. Department of Neurosurgery, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China. jcl6688@163.com. 5. Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin, 150086, China. jcl6688@163.com. 6. Department of Neurosurgery, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China. caijinquan@hrbmu.edu.cn. 7. Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin, 150086, China. caijinquan@hrbmu.edu.cn.
Abstract
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
PURPOSE: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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
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