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SPROUTY-2 and E-cadherin regulate reciprocally and dictate colon cancer cell tumourigenicity

Oncogene volume 29, pages 4800–4813 (2010)Cite this article

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Abstract

SPROUTY-2 (SPRY2) regulates receptor tyrosine kinase signalling and therefore cell growth and differentiation. In this study, we show that SPRY2 expression in colon cancer cells is inhibited by the active vitamin D metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) through E-cadherin-dependent and -independent mechanisms. In turn, SPRY2 represses both basal and 1,25(OH)2D3-induced E-cadherin expression. In line with this, SPRY2 induces ZEB1 RNA and protein, but not that of other epithelial-to-mesenchymal transition inducers that repress the CDH1/E-cadherin promoter. Consistently, SPRY2 and E-cadherin protein levels inversely correlate in colon cancer cell lines and xenografted tumours. Moreover, SPRY2 knockdown by small hairpin RNA increases CDH1/E-cadherin expression and, reciprocally, CDH1/E-cadherin knockdown increases that of SPRY2. In colon cancer patients, SPRY2 is upregulated in undifferentiated high-grade tumours and at the invasive front of low-grade carcinomas. Quantification of protein expression in 34 tumours confirmed an inverse correlation between SPRY2 and E-cadherin. Our data demonstrate a tumourigenic action of SPRY2 that is based on the repression of E-cadherin, probably by the induction of ZEB1, and a reciprocal regulation of SPRY2 and E-cadherin that dictates cell phenotype. We propose SPRY2 as a candidate novel marker for high-grade tumours and a target of therapeutic intervention in colon cancer.

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Abbreviations

1,25(OH)2D3:

1α, 25-dihydroxyvitamin D3

SPRY2:

SPROUTY-2

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Acknowledgements

We thank Drs R Bouillon, A Verstuyf, JP van de Velde, A Fabra, H Clevers, C Carlberg, E Batlle, L Sastre and A García de Herreros for kindly providing us reagents, Dr M Pollán for help with statistical analysis, T Martínez for technical assistance, and R Rycroft for help with the English language editing of the paper. This study was supported by the Ministerio de Ciencia e Innovación of Spain and Fondo Europeo de Desarrollo Regional (SAF2007-60341 and RD06/0020/0009 to AM, RD06/0020/0020 to FB, and SAF2006-04247, RD06/0020/0003 and FIS-Intrasalud (PS09/00562) to JMR), Comunidad de Madrid (S-GEN-0266/2006 to AM and FB), Spanish Association Against Cancer (to JMR), and European Union (MRTN-CT-2005-019496, NucSys, to AM).

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Author notes

  1. P Ordóñez-Morán

    Present address: 6Current address: Cancer Stem Cell Laboratory, École Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland.,

Authors and Affiliations

  1. Departamento de Biología del Cáncer, Instituto de Investigaciones Biomédicas ‘Alberto Sols’, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain

    A Barbáchano, P Ordóñez-Morán, F Pereira, M J Larriba & A Muñoz

  2. Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain

    J M García & F Bonilla

  3. Unidad de Biología Celular, Área de Biología Celular y del Desarrollo, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain

    A Sánchez, N Martínez & J M Rojas

  4. Servicio de Anatomía Patológica, Hospital Universitario Vall d’Hebron, Barcelona, Spain

    J Hernández & S Landolfi

  5. Vall d’Hebron Institut d’Oncología, Barcelona, Spain

    H G Pálmer

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Correspondence to A Muñoz.

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Barbáchano, A., Ordóñez-Morán, P., García, J. et al. SPROUTY-2 and E-cadherin regulate reciprocally and dictate colon cancer cell tumourigenicity. Oncogene 29, 4800–4813 (2010). https://doi.org/10.1038/onc.2010.225

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