EMBO molecular medicine, 2012-01, Vol.4 (1), p.38-51
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.
glioma ; RNAi ; Wnt secretion ; Wnt signalling ; cancer research ; Receptors, G-Protein-Coupled - metabolism ; Humans ; Brain Neoplasms - pathology ; Transcriptome ; Transplantation, Heterologous ; Intracellular Signaling Peptides and Proteins - metabolism ; Wnt Proteins - metabolism ; Brain Neoplasms - metabolism ; Interleukins - metabolism ; Glioma - metabolism ; RNA Interference ; Cell Transformation, Neoplastic - genetics ; Glioma - pathology ; Intracellular Signaling Peptides and Proteins - genetics ; Signal Transduction ; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors ; Cell Transformation, Neoplastic - metabolism ; Cell Cycle Checkpoints ; Animals ; Mice, Nude ; Receptors, G-Protein-Coupled - antagonists & inhibitors ; Cell Line, Tumor ; Mice ; Receptors, G-Protein-Coupled - genetics ; Apoptosis ; Cell Movement ; RNA, Small Interfering - metabolism ; Molecular genetics ; Gliomas ; Oncology, Experimental ; Brain tumors ; Research ; Universities and colleges ; College teachers ; Cells ; Cancer ; Cell proliferation ; Wnt protein ; Pathogenesis ; Secretion ; Brain cancer ; Genomics ; Gene expression ; Kinases ; Experiments ; Proteins ; Signal transduction ; Brain research ; Medical prognosis ; Glioma cells ; Cell cycle ; Ligands ; Tumorigenesis ; Mutation ; Protein transport ; Growth factors ; Cell migration ; Tumors ; Index Medicus
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