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SPROUTY-2 represses the epithelial phenotype of colon carcinoma cells via upregulation of ZEB1 mediated by ETS1 and miR-200/miR-150

Oncogene volume 35, pages 2991–3003 (2016)Cite this article

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Abstract

SPROUTY-2 (SPRY2) is a modulator of tyrosine kinase receptor signaling with receptor- and cell type-dependent inhibitory or enhancing effects. Studies on the action of SPRY2 in major cancers are conflicting and its role remains unclear. Here we have dissected SPRY2 action in human colon cancer. Global transcriptomic analyses show that SPRY2 downregulates genes encoding tight junction proteins such as claudin-7 and occludin and other cell-to-cell and cell-to-matrix adhesion molecules in human SW480-ADH colon carcinoma cells. Moreover, SPRY2 represses LLGL2/HUGL2, PATJ1/INADL and ST14, main regulators of the polarized epithelial phenotype, and ESRP1, an epithelial-to-mesenchymal transition (EMT) inhibitor. A key action of SPRY2 is the upregulation of the major EMT inducer ZEB1, as these effects are reversed by ZEB1 knock-down by means of RNA interference. Consistently, we found an inverse correlation between the expression level of claudin-7 and those of SPRY2 and ZEB1 in human colon tumors. Mechanistically, ZEB1 upregulation by SPRY2 results from the combined induction of ETS1 transcription factor and the repression of microRNAs (miR-200 family, miR-150) that target ZEB1 RNA. Moreover, SPRY2 increased AKT activation by epidermal growth factor, whereas AKT and also Src inhibition reduced the induction of ZEB1. Altogether, these data suggest that AKT and Src are implicated in SPRY2 action. Collectively, these results show a tumorigenic role of SPRY2 in colon cancer that is based on the dysregulation of tight junction and epithelial polarity master genes via upregulation of ZEB1. The dissection of the mechanism of action of SPRY2 in colon cancer cells is important to understand the upregulation of this gene in a subset of patients with this neoplasia that have poor prognosis.

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Acknowledgements

We thank Drs G Goodall, T Brabletz and A García de Herreros for kindly providing us reagents, T Martínez and X Langa for technical assistance and Robin Rycroft for help with the English manuscript. This study was supported by the Ministerio de Economía y Competitividad of Spain and Fondo Europeo de Desarrollo Regional (FEDER) (grant SAF2013-43468-R to AM, SAF2011-29530 to FXR); FEDER-Instituto de Salud Carlos III (RD12/0036/0021 to AM and JMR, RD12/0036/0034 to FXR, RD12/0036/0016 to MS, RD12/0036/0012 to HGP, RD06/0020/0003, PS09/00562 and PI13/00703 to JMR); Comunidad de Madrid (S2010/BMD-2344 Colomics2 to AM); Fundación Científica de la Asociación Española contra el Cáncer (to JMR); US Department of Defense (CA093471 and CA110602 to EH); National Institutes of Health/National Cancer Institute (1R01CA155234-01 to EH); National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (1R21AR062239-01 to EH); and the Melanoma Research Alliance (to EH).

Author information

Author notes

  1. M F Segura

    Present address: 8Present address: Vall d’Hebron Institut de Recerca (VHIR), E-08035 Barcelona, Spain.,

  2. P Ordóñez-Morán

    Present address: 9Present address: Cancer Stem Cell Laboratory, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.,

  3. A Fernández-Barral and F Pereira: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cancer Biology, Instituto de Investigaciones Biomédicas ‘Alberto Sols’, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain

    A Barbáchano, A Fernández-Barral, F Pereira, P Ordóñez-Morán, J M González-Sancho, A Costales-Carrera & A Muñoz

  2. Department of Pathology, New York University School of Medicine, New York, USA

    M F Segura, D Hanniford & E Hernando

  3. Epithelial Carcinogenesis Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

    E Carrillo-de Santa Pau & F X Real

  4. Unidad de Biología Celular, Unidad Funcional de Investigación en Enfermedades Crónicas, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain

    N Martínez & J M Rojas

  5. Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain

    F X Real

  6. Stem cells and Cancer Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain

    H G Pálmer

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Barbáchano, A., Fernández-Barral, A., Pereira, F. et al. SPROUTY-2 represses the epithelial phenotype of colon carcinoma cells via upregulation of ZEB1 mediated by ETS1 and miR-200/miR-150. Oncogene 35, 2991–3003 (2016). https://doi.org/10.1038/onc.2015.366

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