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.

尽管进行了深入的研究，胶质母细胞瘤的预后仍然很差。胶质母细胞瘤干细胞 (GSC) 有助于肿瘤发生、侵袭能力和治疗耐药性。富含亮氨酸重复序列的 G 蛋白偶联受体 5 (Lgr5) 是一种干细胞标记物，参与 GSC 的维持，尽管 Lgr5 阳性 GSC 的特性仍不清楚。在这里，Lgr5-GFP使用了睡美人转座子诱导的胶质母细胞瘤模型敲入小鼠识别来自小鼠胶质母细胞瘤组织的神经球培养物中的 GFP 阳性细胞。全局基因表达分析显示 Gli2 在 GFP 阳性 GSC 中高表达。使用慢病毒介导的 shRNA 敲低 Gli2 可下调 Hedgehog 相关和 Wnt 信号通路相关基因，包括 Lgr5；抑制肿瘤细胞增殖和侵袭能力；并诱导细胞凋亡。GANT61 的药理学 Gli 抑制抑制了肿瘤细胞增殖。在体内原位移植模型中，沉默 Gli2 可抑制 GSC 的致瘤性。这些发现表明 Gli2 影响 Hedgehog 和 Wnt 通路并在 GSC 维持中发挥重要作用，表明 Gli2 可作为胶质母细胞瘤治疗的治疗靶点。