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

• Published in: Cancer gene therapy Vol. 28; no. 12; pp. 1339 - 1352
• Main Authors: Tanigawa, Seisuke, Fujita, Mitsugu, Moyama, Chiami, Ando, Shota, Ii, Hiromi, Kojima, Yasushi, Fujishita, Teruaki, Aoki, Masahiro, Takeuchi, Hayato, Yamanaka, Takumi, Takahashi, Yoshinobu, Hashimoto, Naoya, Nakata, Susumu
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2021; Nature Publishing Group
• Subjects: 13/1; 13/2; 13/31; 13/51; 13/89; 14/34; 38/61; 42/44; 59/5; 631/67/1922; 631/80; 64/60; Analysis; Animals; Apoptosis; Biomedical and Life Sciences; Biomedicine; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - pathology; Carcinogenesis; Care and treatment; Cell growth; Cell Line, Tumor; Cell Proliferation; Diagnosis; Disease Models, Animal; G protein-coupled receptors; Gene Expression; Gene Expression Profiling - methods; Gene Therapy; Glioblastoma; Glioblastoma - genetics; Glioblastoma - pathology; Glioblastoma multiforme; Health aspects; Humans; Identification and classification; Invasiveness; Mice; Observations; Prognosis; Risk factors; Signal transduction; Stem cell transplantation; Stem cells; Therapeutic targets; Transplantation; Tumorigenesis; Tumorigenicity; Wnt protein; Zinc Finger Protein Gli2 - metabolism; Japan
• ISSN: 0929-1903; 1476-5500
• DOI: 10.1038/s41417-020-00282-5

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.