Abstract 3795: Vangl2 and Prickle1 expression, interaction and regulation of Wnt/PCP signaling in medulloblastoma and neuroblastoma.

Abstract

Abstract Background /Aims: Wnt are a family of intercellular signaling factors that regulates a wide range of functions during embryonic development including cell proliferation, cell fate determination, differentiation, cell polarity and cell migration. They bind to Frizzled receptors and thereafter proceed via Dishevelled to several intracellular pathways known as the canonical and non-canonical signaling pathways. Activation of the canonical pathway results in an accumulation of cytoplasmic beta-catenin levels. Increased Wnt/beta-catenin signaling is associated with many forms of cancer, including the embryonic neural childhood tumors medulloblastoma and neuroblastoma. The non-canonical Wnt signaling pathways can inhibit the canonical signaling pathway, although the mechanism is still unclear. In this study, we investigate the roles of Prickle1 and Van Gogh-Like 2 (Vangl2), two planar cell polarity (PCP) genes in regulation of the cytoskeleton, Wnt/beta-catenin activity and tumorigenicity in neuroblastoma and medulloblastoma. Methods: mRNA and protein expression of human Prickle1, Vangl2 and beta-catenin were examined in neuroblastoma and medulloblastoma cell lines. siRNA and cDNA transfection were performed together with co-immunoprecipitation and immunocytochemistry. Results and conclusions: We show that Prickle1 and Vangl2 are expressed in neuroblastoma and medulloblastoma cell lines at different levels. Decreased Prickle1 expression correlates with increased levels of Wnt/beta-catenin in both medullo- and neuroblastoma cell lines, demonstrating a downregulation of PCP components and a possible activation of the canonical Wnt signaling pathway. Immunoprecipitation demonstrated that Prickle1 is present in complex with Vangl2. However, the exact mode of interaction between Prickle1 and Vangl2 remains to be eluciated. Microarray analysis revealed that low expressions of Prickle1 or Vangl2 are both associated significantly worse clinical outcome in neuroblastoma. Additionally, siRNA experiments revealed that knockdown of Prickle1 and Vangl2 increased cell proliferation of neuroblastoma cells. Taken together this indicate that the non-canonical Wnt pathway may be an interesting therapeutic target in embryanol neural childhood tumors. Citation Format: Cecilia H. Dyberg, Panagiotis Papachristou, Hugo Lagercrantz, John I Johnsen, Malin Wickström. Vangl2 and Prickle1 expression, interaction and regulation of Wnt/PCP signaling in medulloblastoma and neuroblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3795. doi:10.1158/1538-7445.AM2013-3795