German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics and Heidelberg University, Faculty of Medicine Mannheim, Department of Cell and Molecular Biology, Heidelberg, Germany.
EMBO Mol Med. 2012 Jan;4(1):38-51. doi: 10.1002/emmm.201100186. Epub 2011 Dec 7.
Malignant astrocytomas are highly aggressive brain tumours with poor prognosis. While a number of structural genomic changes and dysregulation of signalling pathways in gliomas have been described, the identification of biomarkers and druggable targets remains an important task for novel diagnostic and therapeutic approaches. Here, we show that the Wnt-specific secretory protein Evi (also known as GPR177/Wntless/Sprinter) is overexpressed in astrocytic gliomas. Evi/Wls is a core Wnt signalling component and a specific regulator of pan-Wnt protein secretion, affecting both canonical and non-canonical signalling. We demonstrate that its depletion in glioma and glioma-derived stem-like cells led to decreased cell proliferation and apoptosis. Furthermore, Evi/Wls silencing in glioma cells reduced cell migration and the capacity to form tumours in vivo. We further show that Evi/Wls overexpression is sufficient to promote downstream Wnt signalling. Taken together, our study identifies Evi/Wls as an essential regulator of glioma tumourigenesis, identifying a pathway-specific protein trafficking factor as an oncogene and offering novel therapeutic options to interfere with the aberrant regulation of growth factors at the site of production.
恶性星形细胞瘤是一种侵袭性强、预后差的脑肿瘤。虽然已经描述了许多神经胶质瘤中的结构基因组改变和信号通路失调，但鉴定生物标志物和可用药靶点仍然是新型诊断和治疗方法的重要任务。在这里，我们表明 Wnt 特异性分泌蛋白 Evi（也称为 GPR177/Wntless/Sprinter）在星形细胞瘤中过表达。Evi/Wls 是 Wnt 信号通路的核心成分，也是泛 Wnt 蛋白分泌的特定调节剂，影响经典和非经典信号通路。我们证明其在神经胶质瘤和神经胶质瘤衍生的干细胞中的耗竭导致细胞增殖减少和凋亡。此外，Evi/Wls 在神经胶质瘤细胞中的沉默降低了细胞迁移和体内形成肿瘤的能力。我们进一步表明，Evi/Wls 的过表达足以促进下游 Wnt 信号。总之，我们的研究将 Evi/Wls 鉴定为神经胶质瘤发生的重要调节因子，将一种特定于通路的蛋白运输因子鉴定为癌基因，并提供了新的治疗选择来干扰生长因子在产生部位的异常调节。
