4.6 Article

Inhibition of Gli2 suppresses tumorigenicity in glioblastoma stem cells derived from a de novo murine brain cancer model

Journal

CANCER GENE THERAPY
Volume 28, Issue 12, Pages 1339-1352

Publisher

SPRINGERNATURE
DOI: 10.1038/s41417-020-00282-5

Keywords

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Funding

  1. Japan Society for the Promotion of Science [20K07623, 16K08722]
  2. Ministry of Education, Culture, Sports, Science and Technology
  3. Kyoto Pharmaceutical University
  4. Grants-in-Aid for Scientific Research [16K08722, 20K07623] Funding Source: KAKEN

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Recent research has identified Gli2 as a key player in glioblastoma, affecting the Hedgehog and Wnt pathways and contributing to the maintenance of GSCs, suggesting it as a potential therapeutic target for glioblastoma treatment.
The prognosis of glioblastoma remains poor despite intensive research efforts. Glioblastoma stem cells (GSCs) contribute to tumorigenesis, invasive capacity, and therapy resistance. Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5), a stem cell marker, is involved in the maintenance of GSCs, although the properties of Lgr5-positive GSCs remain unclear. Here, the Sleeping-Beauty transposon-induced glioblastoma model was used in Lgr5-GFP knock-in mice identify GFP-positive cells in neurosphere cultures from mouse glioblastoma tissues. Global gene expression analysis showed that Gli2 was highly expressed in GFP-positive GSCs. Gli2 knockdown using lentiviral-mediated shRNA downregulated Hedgehog-related and Wnt signaling pathway-related genes, including Lgr5; suppressed tumor cell proliferation and invasion capacity; and induced apoptosis. Pharmacological Gli inhibition with GANT61 suppressed tumor cell proliferation. Silencing Gli2 suppressed the tumorigenicity of GSCs in an orthotopic transplantation model in vivo. These findings suggest that Gli2 affects the Hedgehog and Wnt pathways and plays an important role in GSC maintenance, suggesting Gli2 as a therapeutic target for glioblastoma treatment.

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