Oncotarget

Research Papers:

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

Karin Zins _, Romana Schäfer, Patrick Paulus, Silvia Dobler, Nazak Fakhari, Mouldy Sioud, Seyedhossein Aharinejad and Dietmar Abraham

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Oncotarget. 2016; 7:46187-46202. https://doi.org/10.18632/oncotarget.10070

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Abstract

Karin Zins1, Romana Schäfer2, Patrick Paulus3, Silvia Dobler3, Nazak Fakhari1, Mouldy Sioud4, Seyedhossein Aharinejad1, Dietmar Abraham1,5

1Division of Cell and Developmental Biology, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, A-1090, Austria

2Apeiron Biologics AG, Vienna, A-1030, Austria

3Department of Anesthesiology and Operative Intensive Care Medicine, Kepler University Hospital, Linz, A-4040, Austria

4Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, N-0310, Norway

5Comprehensive Cancer Center (CCC), Medical University of Vienna, Vienna, A-1090, Austria

Correspondence to:

Dietmar Abraham, email: dietmar.abraham@meduniwien.ac.at

Keywords: Frizzled2, Wnt signaling, neuroblastoma, xenograft model

Received: March 09, 2016     Accepted: May 30, 2016     Published: June 15, 2016

ABSTRACT

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.


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