Frizzled2 signaling regulates growth of high-risk neuroblastomas by interfering with β-catenin-dependent and β-catenin-independent signaling pathways
- Oncotarget. 2016 Jul 19;7(29):46187-46202. doi: 10.18632/oncotarget.10070.
- 1. Division of Cell and Developmental Biology, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, A-1090, Austria.
- 2. Apeiron Biologics AG, Vienna, A-1030, Austria.
- 3. Department of Anesthesiology and Operative Intensive Care Medicine, Kepler University Hospital, Linz, A-4040, Austria.
- 4. Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, N-0310, Norway.
- 5. Comprehensive Cancer Center (CCC), Medical University of Vienna, Vienna, A-1090, Austria.
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.