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The Wnt secretion protein Evi/Gpr177 promotes glioma tumourigenesis.

Augustin I, Goidts V, Bongers A, Kerr G, Vollert G, Radlwimmer B, Hartmann C, Herold-Mende C, Reifenberger G, von Deimling A, Boutros M - EMBO Mol Med (2011)

Bottom Line: Malignant astrocytomas are highly aggressive brain tumours with poor prognosis.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 further show that Evi/Wls overexpression is sufficient to promote downstream Wnt signalling.

View Article: PubMed Central - PubMed

Affiliation: 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. i.augustin@dkfz.de

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The Wnt secretion factor Evi is overexpressed in astrocytic gliomasA. Log2-gene expression ratios normalized to the mean expression in NB samples are shown for diffuse astrocytoma WHO grade II (AII), anaplastic astrocytoma WHO grade III (AAIII), secondary glioblastoma WHO grade IV (sGBIV) and primary glioblastoma WHO grade IV (pGBIV). Median RNA expression is indicated by horizontal bars; boxes show the 25th and 75th percentile range, whiskers mark the 5th and 95th percentiles; maximum and minimum values are depicted as horizontal bars.B, C. The specificity of the antibody against Evi was confirmed by siRNA silencing of the target protein. U87MG cells were transfected with three-independent siRNAs to silence Evi. Silencing of gene expression was validated by Western blot and quantified real-time RT-PCR confirming robust downregulation of Evi expression. β-Actin was detected as loading control. PCR-data are expressed as mean ± SD of three-independent experiments (**p < 0.01).D, E. Representative immunohistochemical stainings for Evi on tissue sections of NB and astrocytic gliomas of different WHO grades. (D) NB, Evi-positive vascular smooth muscle cells; (E) NB, Evi-positive ependymal cells.F, G. Evi-positive tumour cells in a diffuse astrocytoma WHO grade II.H, I. Evi-positive tumour cells in a primary glioblastoma WHO grade IV. Scale bar: 100 µm.
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fig01: The Wnt secretion factor Evi is overexpressed in astrocytic gliomasA. Log2-gene expression ratios normalized to the mean expression in NB samples are shown for diffuse astrocytoma WHO grade II (AII), anaplastic astrocytoma WHO grade III (AAIII), secondary glioblastoma WHO grade IV (sGBIV) and primary glioblastoma WHO grade IV (pGBIV). Median RNA expression is indicated by horizontal bars; boxes show the 25th and 75th percentile range, whiskers mark the 5th and 95th percentiles; maximum and minimum values are depicted as horizontal bars.B, C. The specificity of the antibody against Evi was confirmed by siRNA silencing of the target protein. U87MG cells were transfected with three-independent siRNAs to silence Evi. Silencing of gene expression was validated by Western blot and quantified real-time RT-PCR confirming robust downregulation of Evi expression. β-Actin was detected as loading control. PCR-data are expressed as mean ± SD of three-independent experiments (**p < 0.01).D, E. Representative immunohistochemical stainings for Evi on tissue sections of NB and astrocytic gliomas of different WHO grades. (D) NB, Evi-positive vascular smooth muscle cells; (E) NB, Evi-positive ependymal cells.F, G. Evi-positive tumour cells in a diffuse astrocytoma WHO grade II.H, I. Evi-positive tumour cells in a primary glioblastoma WHO grade IV. Scale bar: 100 µm.

Mentions: Evi is ubiquitously expressed during mouse embryonic development with particular prominent expression in the developing head structures. Expression persists in adult tissues with distinct expression pattern and levels in different organs (Jin et al, 2010; Yu et al, 2010; our unpublished data). Evi is essential for Wnt-dependent developmental processes (Fu et al, 2009). To assess Evi expression during brain tumourigenesis, we analysed an expression profiling database of 71 diffuse astrocytic tumours of different malignancy grades [WHO grade II: n = 8; WHO grade III: n = 11; WHO grade IV (primary glioblastoma: n = 42 and secondary glioblastoma: n = 10)] (Toedt et al, 2011). Strikingly, we found that Evi is strongly overexpressed in astrocytic gliomas of all malignancy grades as compared to control tissue (Fig 1A). This finding was confirmed in an independent data set from the Molecular Brain Neoplasia Database (REMBRANDT) (Madhavan et al, 2009), which also revealed a significant upregulation of Evi transcripts in gliomas. Moreover, higher levels of Evi expression were associated with shorter overall survival of glioma patients (p = 0.013) (Fig S1 of Supporting information). Evi expression levels showed no association with gender, age, TP53, IDH1 or IDH2 mutation status or with MGMT promoter methylation status (data not shown).


The Wnt secretion protein Evi/Gpr177 promotes glioma tumourigenesis.

Augustin I, Goidts V, Bongers A, Kerr G, Vollert G, Radlwimmer B, Hartmann C, Herold-Mende C, Reifenberger G, von Deimling A, Boutros M - EMBO Mol Med (2011)

The Wnt secretion factor Evi is overexpressed in astrocytic gliomasA. Log2-gene expression ratios normalized to the mean expression in NB samples are shown for diffuse astrocytoma WHO grade II (AII), anaplastic astrocytoma WHO grade III (AAIII), secondary glioblastoma WHO grade IV (sGBIV) and primary glioblastoma WHO grade IV (pGBIV). Median RNA expression is indicated by horizontal bars; boxes show the 25th and 75th percentile range, whiskers mark the 5th and 95th percentiles; maximum and minimum values are depicted as horizontal bars.B, C. The specificity of the antibody against Evi was confirmed by siRNA silencing of the target protein. U87MG cells were transfected with three-independent siRNAs to silence Evi. Silencing of gene expression was validated by Western blot and quantified real-time RT-PCR confirming robust downregulation of Evi expression. β-Actin was detected as loading control. PCR-data are expressed as mean ± SD of three-independent experiments (**p < 0.01).D, E. Representative immunohistochemical stainings for Evi on tissue sections of NB and astrocytic gliomas of different WHO grades. (D) NB, Evi-positive vascular smooth muscle cells; (E) NB, Evi-positive ependymal cells.F, G. Evi-positive tumour cells in a diffuse astrocytoma WHO grade II.H, I. Evi-positive tumour cells in a primary glioblastoma WHO grade IV. Scale bar: 100 µm.
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fig01: The Wnt secretion factor Evi is overexpressed in astrocytic gliomasA. Log2-gene expression ratios normalized to the mean expression in NB samples are shown for diffuse astrocytoma WHO grade II (AII), anaplastic astrocytoma WHO grade III (AAIII), secondary glioblastoma WHO grade IV (sGBIV) and primary glioblastoma WHO grade IV (pGBIV). Median RNA expression is indicated by horizontal bars; boxes show the 25th and 75th percentile range, whiskers mark the 5th and 95th percentiles; maximum and minimum values are depicted as horizontal bars.B, C. The specificity of the antibody against Evi was confirmed by siRNA silencing of the target protein. U87MG cells were transfected with three-independent siRNAs to silence Evi. Silencing of gene expression was validated by Western blot and quantified real-time RT-PCR confirming robust downregulation of Evi expression. β-Actin was detected as loading control. PCR-data are expressed as mean ± SD of three-independent experiments (**p < 0.01).D, E. Representative immunohistochemical stainings for Evi on tissue sections of NB and astrocytic gliomas of different WHO grades. (D) NB, Evi-positive vascular smooth muscle cells; (E) NB, Evi-positive ependymal cells.F, G. Evi-positive tumour cells in a diffuse astrocytoma WHO grade II.H, I. Evi-positive tumour cells in a primary glioblastoma WHO grade IV. Scale bar: 100 µm.
Mentions: Evi is ubiquitously expressed during mouse embryonic development with particular prominent expression in the developing head structures. Expression persists in adult tissues with distinct expression pattern and levels in different organs (Jin et al, 2010; Yu et al, 2010; our unpublished data). Evi is essential for Wnt-dependent developmental processes (Fu et al, 2009). To assess Evi expression during brain tumourigenesis, we analysed an expression profiling database of 71 diffuse astrocytic tumours of different malignancy grades [WHO grade II: n = 8; WHO grade III: n = 11; WHO grade IV (primary glioblastoma: n = 42 and secondary glioblastoma: n = 10)] (Toedt et al, 2011). Strikingly, we found that Evi is strongly overexpressed in astrocytic gliomas of all malignancy grades as compared to control tissue (Fig 1A). This finding was confirmed in an independent data set from the Molecular Brain Neoplasia Database (REMBRANDT) (Madhavan et al, 2009), which also revealed a significant upregulation of Evi transcripts in gliomas. Moreover, higher levels of Evi expression were associated with shorter overall survival of glioma patients (p = 0.013) (Fig S1 of Supporting information). Evi expression levels showed no association with gender, age, TP53, IDH1 or IDH2 mutation status or with MGMT promoter methylation status (data not shown).

Bottom Line: Malignant astrocytomas are highly aggressive brain tumours with poor prognosis.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 further show that Evi/Wls overexpression is sufficient to promote downstream Wnt signalling.

View Article: PubMed Central - PubMed

Affiliation: 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. i.augustin@dkfz.de

Show MeSH
Related in: MedlinePlus