Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

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

Oncogene volume 33, pages 1975–1985 (2014)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D . Global cancer statistics. CA: A Cancer Journal for Clinicians 2011; 61 (2): 69–90.

    Google Scholar 

  2. Kinzler KW, Vogelstein B . Lessons from hereditary colorectal cancer. Cell 1996; 87: 159–170.

    Article  CAS  Google Scholar 

  3. van de Wetering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A et al. The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 2002; 111: 241–250.

    Article  CAS  Google Scholar 

  4. Palmer HG . Vitamin D3 promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. J Cell Biol 2001; 154: 369–388.

    Article  CAS  Google Scholar 

  5. Palmer HG, Anjos-Afonso F, Carmeliet G, Takeda H, Watt FM . The vitamin D receptor is a Wnt effector that controls hair follicle differentiation and specifies tumor type in adult epidermis. PLoS ONE 2008; 3: e1483.

    Article  Google Scholar 

  6. Olson LE, Tollkuhn J, Scafoglio C, Krones A, Zhang J, Ohgi KA et al. Homeodomain-mediated beta-catenin-dependent switching events dictate cell-lineage determination. Cell 2006; 125: 593–605.

    Article  CAS  Google Scholar 

  7. Mulholland DJ, Dedhar S, Coetzee GA, Nelson CC . Interaction of nuclear receptors with the Wnt/beta-catenin/Tcf signaling axis: Wnt you like to know? Endocr Rev. Endocr Rev 2005; 26: 898–915.

    Article  CAS  Google Scholar 

  8. Tenbaum SP, Ordonez-Moran P, Puig I, Chicote I, Arques O, Landolfi S et al. beta-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer. Nat Med 2012; 18: 892–901.

    Article  CAS  Google Scholar 

  9. Calnan DR, Brunet A . The FoxO code. Oncogene 2008; 27: 2276–2288.

    Article  CAS  Google Scholar 

  10. Hoogeboom D, Essers MA, Polderman PE, Voets E, Smits LM, Burgering BM . Interaction of FOXO with beta-catenin inhibits beta-catenin/T cell factor activity. J Biol Chem 2008; 283: 9224–9230.

    Article  CAS  Google Scholar 

  11. Essers MA, de Vries-Smits LM, Barker N, Polderman PE, Burgering BM, Korswagen HC . Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science 2005; 308: 1181–1184.

    Article  CAS  Google Scholar 

  12. Paik JH, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z et al. FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 2007; 128: 309–323.

    Article  CAS  Google Scholar 

  13. Lo TL, Fong CW, Yusoff P, McKie AB, Chua MS, Leung HY et al. Sprouty and cancer: the first terms report. Cancer lett 2006; 242: 141–150.

    Article  CAS  Google Scholar 

  14. Fong CW, Chua MS, McKie AB, Ling SH, Mason V, Li R et al. Sprouty 2, an inhibitor of mitogen-activated protein kinase signaling, is down-regulated in hepatocellular carcinoma. Cancer Res 2006; 66: 2048–2058.

    Article  CAS  Google Scholar 

  15. Sanchez A, Setien F, Martinez N, Oliva JL, Herranz M, Fraga MF et al. Epigenetic inactivation of the ERK inhibitor Spry2 in B-cell diffuse lymphomas. Oncogene 2008; 27: 4969–4972.

    Article  CAS  Google Scholar 

  16. Frank MJ, Dawson DW, Bensinger SJ, Hong JS, Knosp WM, Xu L et al. Expression of sprouty2 inhibits B-cell proliferation and is epigenetically silenced in mouse and human B-cell lymphomas. Blood 2009; 113: 2478–2487.

    Article  CAS  Google Scholar 

  17. Song K, Gao Q, Zhou J, Qiu SJ, Huang XW, Wang XY et al. Prognostic significance and clinical relevance of Sprouty 2 protein expression in human hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2012; 11: 177–184.

    Article  CAS  Google Scholar 

  18. Bloethner S, Chen B, Hemminki K, Muller-Berghaus J, Ugurel S, Schadendorf D et al. Effect of common B-RAF and N-RAS mutations on global gene expression in melanoma cell lines. Carcinogenesis 2005; 26: 1224–1232.

    Article  CAS  Google Scholar 

  19. Tsavachidou D, Coleman ML, Athanasiadis G, Li S, Licht JD, Olson MF et al. SPRY2 is an inhibitor of the ras/extracellular signal-regulated kinase pathway in melanocytes and melanoma cells with wild-type BRAF but not with the V599E mutant. Cancer Res 2004; 64: 5556–5559.

    Article  CAS  Google Scholar 

  20. Barbachano A, Ordonez-Moran P, Garcia JM, Sanchez A, Pereira F, Larriba MJ et al. SPROUTY-2 and E-cadherin regulate reciprocally and dictate colon cancer cell tumourigenicity. Oncogene 2010; 29: 4800–4813.

    Article  CAS  Google Scholar 

  21. Holgren C, Dougherty U, Edwin F, Cerasi D, Taylor I, Fichera A et al. Sprouty-2 controls c-Met expression and metastatic potential of colon cancer cells: sprouty/c-Met upregulation in human colonic adenocarcinomas. Oncogene 2010; 29: 5241–5253.

    Article  CAS  Google Scholar 

  22. Silva-Vargas V, Lo Celso C, Giangreco A, Ofstad T, Prowse DM, Braun KM et al. Beta-catenin and Hedgehog signal strength can specify number and location of hair follicles in adult epidermis without recruitment of bulge stem cells. Dev Cell 2005; 9: 121–131.

    Article  CAS  Google Scholar 

  23. Dijkers PF, Medema RH, Lammers JW, Koenderman L, Coffer PJ . Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr Biol 2000; 10: 1201–1204.

    Article  CAS  Google Scholar 

  24. Impagnatiello MA, Weitzer S, Gannon G, Compagni A, Cotten M, Christofori G . Mammalian sprouty-1 and -2 are membrane-anchored phosphoprotein inhibitors of growth factor signaling in endothelial cells. J Cell Biol 2001; 152: 1087–1098.

    Article  CAS  Google Scholar 

  25. DaSilva J, Xu L, Kim HJ, Miller WT, Bar-Sagi D . Regulation of sprouty stability by Mnk1-dependent phosphorylation. Mol Cell Biol 2006; 26: 1898–1907.

    Article  CAS  Google Scholar 

  26. Lao DH, Yusoff P, Chandramouli S, Philp RJ, Fong CW, Jackson RA et al. Direct binding of PP2A to Sprouty2 and phosphorylation changes are a prerequisite for ERK inhibition downstream of fibroblast growth factor receptor stimulation. J Biol Chem 2007; 282: 9117–9126.

    Article  CAS  Google Scholar 

  27. Van der Flier LG, Sabates-Bellver J, Oving I, Haegebarth A, De Palo M, Anti M et al. The intestinal Wnt/TCF signature. Gastroenterology 2007; 132: 628–632.

    Article  CAS  Google Scholar 

  28. Fevr T, Robine S, Louvard D, Huelsken J . Wnt/beta-catenin is essential for intestinal homeostasis and maintenance of intestinal stem cells. Mol Cell Biol 2007; 27: 7551–7559.

    Article  CAS  Google Scholar 

  29. Mason JM, Morrison DJ, Basson MA, Licht JD . Sprouty proteins: multifaceted negative-feedback regulators of receptor tyrosine kinase signaling. Trends Cell Biol 2006; 16: 45–54.

    Article  CAS  Google Scholar 

  30. Christofori G . Split personalities: the agonistic antagonist Sprouty. Nat Cell Biol 2003; 5: 377–379.

    Article  CAS  Google Scholar 

  31. Guy GR, Jackson RA, Yusoff P, Chow SY . Sprouty proteins: modified modulators, matchmakers or missing links? J Endocrinol 2009; 203: 191–202.

    Article  CAS  Google Scholar 

  32. Cabrita MA, Christofori G . Sprouty proteins, masterminds of receptor tyrosine kinase signaling. Angiogenesis 2008; 11: 53–62.

    Article  CAS  Google Scholar 

  33. Fiske WH, Threadgill D, Coffey RJ . ERBBs in the gastrointestinal tract: recent progress and new perspectives. Exp Cell Res 2009; 315: 583–601.

    Article  CAS  Google Scholar 

  34. Fong CW, Leong HF, Wong ES, Lim J, Yusoff P, Guy GR . Tyrosine phosphorylation of Sprouty2 enhances its interaction with c-Cbl and is crucial for its function. J Biol Chem 2003; 278: 33456–33464.

    Article  CAS  Google Scholar 

  35. Wong ES, Fong CW, Lim J, Yusoff P, Low BC, Langdon WY et al. Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequently enhances Ras/ERK signalling. Embo J 2002; 21: 4796–4808.

    Article  CAS  Google Scholar 

  36. Haglund K, Schmidt MH, Wong ES, Guy GR, Dikic I . Sprouty2 acts at the Cbl/CIN85 interface to inhibit epidermal growth factor receptor downregulation. EMBO Rep 2005; 6: 635–641.

    Article  CAS  Google Scholar 

  37. Kim HJ, Taylor LJ, Bar-Sagi D . Spatial regulation of EGFR signaling by Sprouty2. Curr Biol 2007; 17: 455–461.

    Article  CAS  Google Scholar 

  38. Egan JE, Hall AB, Yatsula BA, Bar-Sagi D . The bimodal regulation of epidermal growth factor signaling by human Sprouty proteins. Proc Natl Acad Sci USA 2002; 99: 6041–6046.

    Article  CAS  Google Scholar 

  39. Hanafusa H, Torii S, Yasunaga T, Nishida E Sprouty1 . and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway. Nat Cell Biol 2002; 4: 850–858.

    Article  CAS  Google Scholar 

  40. Schneider MR, Werner S, Paus R, Wolf E . Beyond wavy hairs: the epidermal growth factor receptor and its ligands in skin biology and pathology. Am J Pathol 2008; 173: 14–24.

    Article  CAS  Google Scholar 

  41. Barker N, Clevers H . Tracking down the stem cells of the intestine: strategies to identify adult stem cells. Gastroenterology 2007; 133: 1755–1760.

    Article  CAS  Google Scholar 

  42. Watt FM, Jensen KB . Epidermal stem cell diversity and quiescence. EMBO Mol Med 2009; 1: 260–267.

    Article  CAS  Google Scholar 

  43. Jensen KB, Collins CA, Nascimento E, Tan DW, Frye M, Itami S et al. Lrig1 expression defines a distinct multipotent stem cell population in mammalian epidermis. Cell stem cell 2009; 4: 427–439.

    Article  CAS  Google Scholar 

  44. Shim K, Minowada G, Coling DE, Martin GR . Sprouty2, a mouse deafness gene, regulates cell fate decisions in the auditory sensory epithelium by antagonizing FGF signaling. Dev Cell 2005; 8: 553–564.

    Article  CAS  Google Scholar 

  45. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351: 337–345.

    Article  CAS  Google Scholar 

  46. Dijkers PF, Medema RH, Pals C, Banerji L, Thomas NS, Lam EW et al. Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27(KIP1). Mol Cell Biol 2000; 20: 9138–9148.

    Article  CAS  Google Scholar 

  47. Raghav SK, Deplancke B . Genome-wide profiling of DNA-binding proteins using barcode-based multiplex Solexa sequencing. Methods Mol Biol 2012; 786: 247–262.

    Article  CAS  Google Scholar 

  48. Filali M, Cheng N, Abbott D, Leontiev V, Engelhardt JF . Wnt-3A/beta-catenin signaling induces transcription from the LEF-1 promoter. J Biol Chem 2002; 6 277: 33398–33410.

    Article  Google Scholar 

  49. Ding W, Bellusci S, Shi W, Warburton D . Functional analysis of the human Sprouty2 gene promoter. Gene 2003; 322: 175–185.

    Article  CAS  Google Scholar 

  50. Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW et al. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC−/− colon carcinoma. Science 1997; 275 1784-7.

    Article  CAS  Google Scholar 

  51. Oriol A, Irene C, Stephan T, Isabel P, Héctor GP . Standardized Relative Quantification of Immunofluorescence Tissue Staining. H.G. Palmer's Lab, Stem Cells and Cancer. Protocol Exchange (e-pub ahead of print 2 April 2012).

Download references

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.

Author information

Author notes

  1. A Irmisch and A Barbáchano: These authors contributed equally to this work.

Authors and Affiliations

  1. Instituto de Investigaciones Biomédicas 'Alberto Sols', Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain

    P Ordóñez-Morán, A Barbáchano & A Muñoz

  2. Swiss Institute for Experimental Cancer Research, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

    P Ordóñez-Morán, A Irmisch & J Huelsken

  3. Stem Cells and Cancer Laboratory, Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

    I Chicote, S Tenbaum & H G Pálmer

  4. Department of Pathology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain

    S Landolfi

  5. Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain

    J Tabernero

Authors
  1. P Ordóñez-Morán
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Irmisch
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Barbáchano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. I Chicote
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Tenbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S Landolfi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Tabernero
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J Huelsken
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A Muñoz
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. H G Pálmer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H G Pálmer.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.140

Keywords

This article is cited by

Search

Advanced search

Quick links