Frizzled2 signaling regulates growth of high-risk neuroblastomas by interfering with β-catenin-dependent and β-catenin-independent signaling pathways
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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
Dietmar Abraham, email: firstname.lastname@example.org
Keywords: Frizzled2, Wnt signaling, neuroblastoma, xenograft model
Received: March 09, 2016 Accepted: May 30, 2016 Published: June 15, 2016
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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