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SPROUTY2 is a β-catenin and FOXO3a target gene indicative of poor prognosis in colon cancer

Abstract

SPROUTY2 (SPRY2) is an intracellular regulator of receptor tyrosine kinase signaling involved in cell growth, differentiation and tumorigenesis. Here, we show that SPRY2 is a target gene of the Wnt/β-catenin pathway that is abnormally activated in more than 90% of colon carcinomas. In human colon cancer cells, SPRY2 expression is induced by β-catenin in co-operation with the transcription factor FOXO3a instead of lymphoid enhancer factor/T-cell factor proteins. We found binding of β-catenin to the SPRY2 promoter at FOXO3a response elements. In vivo, cells marked by nuclear β-catenin and FOXO3a express SPRY2 in proliferative epithelial tissues, such as intestinal mucosa and epidermis. Consistently, inducible β-catenin deletion in mice reduced Spry2 expression in the small intestine. Moreover, SPRY2 protein expression correlated with nuclear β-catenin and FOXO3a colocalization in human colon carcinomas. Importantly, the amount of SPRY2 protein correlated with shorter overall survival of colon cancer patients. Our data reveal SPRY2 as a novel Wnt/β-catenin and FOXO3a target gene indicative of poor prognosis in colon cancer.

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Acknowledgements

We thank T Martínez for technical assistance and Hans Clevers for providing the LS174T-tetOn-ΔNTCF4 cells. Experiments were supported by grants from Fondo Europeo de Desarrollo Regional-Instituto de Salud Carlos III and Spanish Cooperative Research Network on Cancer (RTICC) (FIS-PI081356, RD12/0036/0001, RD12/0036/0021 and RD12/0036/0012), Plan Nacional de Biomedicina, Ministerio de Economía y Competitividad (SAF-18302) and Comunidad de Madrid (S2010/BMD-2344 Colomics2). HGP was supported by the Miguel Servet Program, Instituto de Salud Carlos III (ISCIII) and PO-M by an EMBO research fellowship.

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Ordóñez-Morán, P., Irmisch, A., Barbáchano, A. et al. SPROUTY2 is a β-catenin and FOXO3a target gene indicative of poor prognosis in colon cancer. Oncogene 33, 1975–1985 (2014). https://doi.org/10.1038/onc.2013.140

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