Cargando…

Frizzled2 signaling regulates growth of high-risk neuroblastomas by interfering with β-catenin-dependent and β-catenin-independent signaling pathways

Frizzled2 (FZD2) is a receptor for Wnts and may activate both canonical and non-canonical Wnt signaling pathways in cancer. However, no studies have reported an association between FZD2 signaling and high-risk NB so far. Here we report that FZD2 signaling pathways are critical to NB growth in MYCN-s...

Descripción completa

Detalles Bibliográficos
Autores principales: Zins, Karin, Schäfer, Romana, Paulus, Patrick, Dobler, Silvia, Fakhari, Nazak, Sioud, Mouldy, Aharinejad, Seyedhossein, Abraham, Dietmar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216790/
https://www.ncbi.nlm.nih.gov/pubmed/27323822
http://dx.doi.org/10.18632/oncotarget.10070
_version_ 1782491983257796608
author Zins, Karin
Schäfer, Romana
Paulus, Patrick
Dobler, Silvia
Fakhari, Nazak
Sioud, Mouldy
Aharinejad, Seyedhossein
Abraham, Dietmar
author_facet Zins, Karin
Schäfer, Romana
Paulus, Patrick
Dobler, Silvia
Fakhari, Nazak
Sioud, Mouldy
Aharinejad, Seyedhossein
Abraham, Dietmar
author_sort Zins, Karin
collection PubMed
description Frizzled2 (FZD2) is a receptor for Wnts and may activate both canonical and non-canonical Wnt signaling pathways in cancer. However, no studies have reported an association between FZD2 signaling and high-risk NB so far. Here we report that FZD2 signaling pathways are critical to NB growth in MYCN-single copy SK-N-AS and MYCN-amplified SK-N-DZ high-risk NB cells. We demonstrate that stimulation of FZD2 by Wnt3a and Wnt5a regulates β-catenin-dependent and –independent Wnt signaling factors. FZD2 blockade suppressed β-catenin-dependent signaling activity and increased phosphorylation of PKC, AKT and ERK in vitro, consistent with upregulation of β-catenin-independent signaling activity. Finally, FZD2 small interfering RNA knockdown suppressed tumor growth in murine NB xenograft models associated with suppressed β-catenin-dependent signaling and a less vascularized phenotype in both NB xenografts. Together, our study suggests a role for FZD2 in high-risk NB cell growth and provides a potential candidate for therapeutic inhibition in FZD2-expressing NB patients.
format Online
Article
Text
id pubmed-5216790
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-52167902017-01-15 Frizzled2 signaling regulates growth of high-risk neuroblastomas by interfering with β-catenin-dependent and β-catenin-independent signaling pathways Zins, Karin Schäfer, Romana Paulus, Patrick Dobler, Silvia Fakhari, Nazak Sioud, Mouldy Aharinejad, Seyedhossein Abraham, Dietmar Oncotarget Research Paper Frizzled2 (FZD2) is a receptor for Wnts and may activate both canonical and non-canonical Wnt signaling pathways in cancer. However, no studies have reported an association between FZD2 signaling and high-risk NB so far. Here we report that FZD2 signaling pathways are critical to NB growth in MYCN-single copy SK-N-AS and MYCN-amplified SK-N-DZ high-risk NB cells. We demonstrate that stimulation of FZD2 by Wnt3a and Wnt5a regulates β-catenin-dependent and –independent Wnt signaling factors. FZD2 blockade suppressed β-catenin-dependent signaling activity and increased phosphorylation of PKC, AKT and ERK in vitro, consistent with upregulation of β-catenin-independent signaling activity. Finally, FZD2 small interfering RNA knockdown suppressed tumor growth in murine NB xenograft models associated with suppressed β-catenin-dependent signaling and a less vascularized phenotype in both NB xenografts. Together, our study suggests a role for FZD2 in high-risk NB cell growth and provides a potential candidate for therapeutic inhibition in FZD2-expressing NB patients. Impact Journals LLC 2016-06-15 /pmc/articles/PMC5216790/ /pubmed/27323822 http://dx.doi.org/10.18632/oncotarget.10070 Text en Copyright: © 2016 Zins et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Zins, Karin
Schäfer, Romana
Paulus, Patrick
Dobler, Silvia
Fakhari, Nazak
Sioud, Mouldy
Aharinejad, Seyedhossein
Abraham, Dietmar
Frizzled2 signaling regulates growth of high-risk neuroblastomas by interfering with β-catenin-dependent and β-catenin-independent signaling pathways
title Frizzled2 signaling regulates growth of high-risk neuroblastomas by interfering with β-catenin-dependent and β-catenin-independent signaling pathways
title_full Frizzled2 signaling regulates growth of high-risk neuroblastomas by interfering with β-catenin-dependent and β-catenin-independent signaling pathways
title_fullStr Frizzled2 signaling regulates growth of high-risk neuroblastomas by interfering with β-catenin-dependent and β-catenin-independent signaling pathways
title_full_unstemmed Frizzled2 signaling regulates growth of high-risk neuroblastomas by interfering with β-catenin-dependent and β-catenin-independent signaling pathways
title_short Frizzled2 signaling regulates growth of high-risk neuroblastomas by interfering with β-catenin-dependent and β-catenin-independent signaling pathways
title_sort frizzled2 signaling regulates growth of high-risk neuroblastomas by interfering with β-catenin-dependent and β-catenin-independent signaling pathways
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216790/
https://www.ncbi.nlm.nih.gov/pubmed/27323822
http://dx.doi.org/10.18632/oncotarget.10070
work_keys_str_mv AT zinskarin frizzled2signalingregulatesgrowthofhighriskneuroblastomasbyinterferingwithbcatenindependentandbcateninindependentsignalingpathways
AT schaferromana frizzled2signalingregulatesgrowthofhighriskneuroblastomasbyinterferingwithbcatenindependentandbcateninindependentsignalingpathways
AT pauluspatrick frizzled2signalingregulatesgrowthofhighriskneuroblastomasbyinterferingwithbcatenindependentandbcateninindependentsignalingpathways
AT doblersilvia frizzled2signalingregulatesgrowthofhighriskneuroblastomasbyinterferingwithbcatenindependentandbcateninindependentsignalingpathways
AT fakharinazak frizzled2signalingregulatesgrowthofhighriskneuroblastomasbyinterferingwithbcatenindependentandbcateninindependentsignalingpathways
AT sioudmouldy frizzled2signalingregulatesgrowthofhighriskneuroblastomasbyinterferingwithbcatenindependentandbcateninindependentsignalingpathways
AT aharinejadseyedhossein frizzled2signalingregulatesgrowthofhighriskneuroblastomasbyinterferingwithbcatenindependentandbcateninindependentsignalingpathways
AT abrahamdietmar frizzled2signalingregulatesgrowthofhighriskneuroblastomasbyinterferingwithbcatenindependentandbcateninindependentsignalingpathways