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Heterogeneity of Jagged1 expression in human and mouse intestinal tumors: implications for targeting Notch signaling

Oncogene volume 29, pages 992–1002 (2010)Cite this article

Abstract

Inhibition of Notch signaling is effective in inhibiting colon tumorigenesis, but targeting specific components of the pathway may provide more effective strategies. Here we show that the expression of Jagged1, a ligand for canonical Notch signaling, was restricted to enteroendocrine cells or undetectable in the mucosa of the human small and large intestine, respectively. In contrast, increased expression characterized half of human colon tumors, although not all tumors with elevated Wnt signaling displayed elevated Jagged1. Increased Jagged1 was also present in intestinal tumors of Apc1638N/+ and ApcMin/+ mice, but to a higher level and more frequently in the former, and in 90% of mouse tumors Notch signaling was elevated when Jagged1 was elevated. In the human HT29Cl16E colonic carcinoma cell line, induction of goblet cell differentiation by contact inhibition of growth depended on the loss of Jagged1-mediated Notch activation, with signaling through Notch1 and Notch2 acting redundantly. Therefore, targeting of Jagged1 could be effective in downregulating Notch signaling in a subset of tumors, but may avoid the limiting gastrointestinal toxicity caused by pharmacological inhibition of Notch signaling.

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References

  • Akiyoshi T, Nakamura M, Yanai K, Nagai S, Wada J, Koga K et al. (2008). Gamma-secretase inhibitors enhance taxane-induced mitotic arrest and apoptosis in colon cancer cells. Gastroenterology 134: 131–144.

    Article  CAS  PubMed  Google Scholar 

  • Augenlicht LH, Augeron C, Yander G, Laboisse C . (1987). Overexpression of ras in mucus-secreting human colon carcinoma cells of low tumorigenicity. Cancer Res 47: 3763–3765.

    CAS  PubMed  Google Scholar 

  • Augeron C, Laboisse CL . (1984). Emergence of permanently differentiated cell clones in a human colonic cancer cell line in culture after treatment with sodium butyrate. Cancer Res 44: 3961–3969.

    CAS  PubMed  Google Scholar 

  • Estrach S, Ambler CA, Lo Celso C, Hozumi K, Watt FM . (2006). Jagged 1 is a beta-catenin target gene required for ectopic hair follicle formation in adult epidermis. Development 133: 4427–4438.

    Article  CAS  PubMed  Google Scholar 

  • Fodde R, Edelmann W, Yang K, van Leeuwen C, Carlson C, Renault B et al. (1994). A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors. Proc Natl Acad Sci USA 91: 8969–8973.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fortini ME, Artavanis-Tsakonas S . (1994). The suppressor of hairless protein participates in notch receptor signaling. Cell 79: 273–282.

    Article  CAS  PubMed  Google Scholar 

  • Fre S, Huyghe M, Mourikis P, Robine S, Louvard D, Artavanis-Tsakonas S . (2005). Notch signals control the fate of immature progenitor cells in the intestine. Nature 435: 964–968.

    Article  CAS  PubMed  Google Scholar 

  • Fre S, Pallavi SK, Huyghe M, Lae M, Janssen KP, Robine S et al. (2009). Notch and Wnt signals cooperatively control cell proliferation and tumorigenesis in the intestine. Proc Natl Acad Sci USA 106: 6309–6314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fre S, Vignjevic D, Schoumacher M, Duffy SL, Janssen KP, Robine S et al. (2008). Epithelial morphogenesis and intestinal cancer: new insights in signaling mechanisms. Adv Cancer Res 100: 85–111.

    Article  CAS  PubMed  Google Scholar 

  • Fryer CJ, Lamar E, Turbachova I, Kintner C, Jones KA . (2002). Mastermind mediates chromatin-specific transcription and turnover of the Notch enhancer complex. Genes Dev 16: 1397–1411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghaleb AM, Aggarwal G, Bialkowska AB, Nandan MO, Yang VW . (2008). Notch inhibits expression of the Kruppel-like factor 4 tumor suppressor in the intestinal epithelium. Mol Cancer Res 6: 1920–1927.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guilmeau S, Flandez M, Bancroft L, Sellers R, Tear B, Stanley P et al. (2008). Intestinal deletion of protein O-fucosyltransferase in the mouse inhibits Notch signaling and causes enterocolitis. Gastroenterology 135: 849–860.

    Article  CAS  PubMed  Google Scholar 

  • Jarriault S, Brou C, Logeat F, Schroeter EH, Kopan R, Israel A . (1995). Signalling downstream of activated mammalian Notch. Nature 377: 355–358.

    Article  CAS  PubMed  Google Scholar 

  • Jensen J, Pedersen EE, Galante P, Hald J, Heller RS, Ishibashi M et al. (2000). Control of endodermal endocrine development by Hes-1. Nat Genet 24: 36–44.

    Article  CAS  PubMed  Google Scholar 

  • Katoh M, Katoh M . (2006). Notch ligand, JAG1, is evolutionarily conserved target of canonical WNT signaling pathway in progenitor cells. Int J Mol Med 17: 681–685.

    CAS  PubMed  Google Scholar 

  • Laburthe M, Augeron C, Rouyer-Fessard C, Roumagnac I, Maoret JJ, Grasset E et al. (1989). Functional VIP receptors in the human mucus-secreting colonic epithelial cell line CL 16E. Am J Physiol 256: G443–G450.

    CAS  PubMed  Google Scholar 

  • Levy DB, Smith KJ, Beazer-Barclay Y, Hamilton SR, Vogelstein B, Kinzler KW . (1994). Inactivation of both APC alleles in human and mouse tumors. Cancer Res 54: 5953–5958.

    CAS  PubMed  Google Scholar 

  • Martys-Zage JL, Kim SH, Berechid B, Bingham SJ, Chu S, Sklar J et al. (2000). Requirement for presenilin 1 in facilitating lagged 2-mediated endoproteolysis and signaling of notch 1. J Mol Neurosci 15: 189–204.

    Article  CAS  PubMed  Google Scholar 

  • McCarthy JV . (2005). Involvement of presenilins in cell-survival signalling pathways. Biochem Soc Trans 33: 568–572.

    Article  CAS  PubMed  Google Scholar 

  • Merlin D, Augeron C, Tien XY, Guo X, Laboisse CL, Hopfer U . (1994). ATP-stimulated electrolyte and mucin secretion in the human intestinal goblet cell line HT29-Cl.16E. J Membr Biol 137: 137–149.

    Article  CAS  PubMed  Google Scholar 

  • Milano J, McKay J, Dagenais C, Foster-Brown L, Pognan F, Gadient R et al. (2004). Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol Sci 82: 341–358.

    Article  CAS  PubMed  Google Scholar 

  • Moser AR, Pitot HC, Dove WF . (1990). A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247: 322–324.

    Article  CAS  PubMed  Google Scholar 

  • Ohlstein B, Spradling A . (2006). The adult Drosophila posterior midgut is maintained by pluripotent stem cells. Nature 439: 470–474.

    Article  CAS  PubMed  Google Scholar 

  • Riccio O, van Gijn ME, Bezdek AC, Pellegrinet L, van Es JH, Zimber-Strobl U et al. (2008). Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2. EMBO Rep 9: 377–383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rodilla V, Villanueva A, Obrador-Hevia A, Robert-Moreno A, Fernandez-Majada V, Grilli A et al. (2009). Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer. Proc Natl Acad Sci USA 106: 6315–6320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sander GR, Powell BC . (2004). Expression of notch receptors and ligands in the adult gut. J Histochem Cytochem 52: 509–516.

    Article  CAS  PubMed  Google Scholar 

  • Shroyer NF, Helmrath MA, Wang VY, Antalffy B, Henning SJ, Zoghbi HY . (2007). Intestine-specific ablation of mouse atonal homolog 1 (Math1) reveals a role in cellular homeostasis. Gastroenterology 132: 2478–2488.

    Article  CAS  PubMed  Google Scholar 

  • Smits R, Kartheuser A, Jagmohan-Changur S, Leblanc V, Breukel C, de Vries A et al. (1997). Loss of Apc and the entire chromosome 18 but absence of mutations at the Ras and Tp53 genes in intestinal tumors from Apc1638N, a mouse model for Apc-driven carcinogenesis. Carcinogenesis 18: 321–327.

    Article  CAS  PubMed  Google Scholar 

  • Stanger BZ, Datar R, Murtaugh LC, Melton DA . (2005). Direct regulation of intestinal fate by Notch. Proc Natl Acad Sci USA 102: 12443–12448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Strobl LJ, Hofelmayr H, Stein C, Marschall G, Brielmeier M, Laux G et al. (1997). Both Epstein–Barr viral nuclear antigen 2 (EBNA2) and activated Notch1 transactivate genes by interacting with the cellular protein RBP-J kappa. Immunobiology 198: 299–306.

    Article  CAS  PubMed  Google Scholar 

  • Takebayashi K, Sasai Y, Sakai Y, Watanabe T, Nakanishi S, Kageyama R . (1994). Structure, chromosomal locus, and promoter analysis of the gene encoding the mouse helix-loop-helix factor HES-1. Negative autoregulation through the multiple N box elements. J Biol Chem 269: 5150–5156.

    CAS  PubMed  Google Scholar 

  • van Es JH, van Gijn ME, Riccio O, van den Born M, Vooijs M, Begthel H et al. (2005). Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435: 959–963.

    Article  CAS  PubMed  Google Scholar 

  • Velcich A, Corner G, Paul D, Zhuang M, Mariadason JM, Laboisse C et al. (2005). Quantitative rather than qualitative differences in gene expression predominate in intestinal cell maturation along distinct cell lineages. Exp Cell Res 304: 28–39.

    Article  CAS  PubMed  Google Scholar 

  • Wheeler JM, Warren BF, Mortensen NJ, Kim HC, Biddolph SC, Elia G et al. (2002). An insight into the genetic pathway of adenocarcinoma of the small intestine. Gut 50: 218–223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang Q, Bermingham NA, Finegold MJ, Zoghbi HY . (2001). Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science 294: 2155–2158.

    Article  CAS  PubMed  Google Scholar 

  • Zheng J, Shou J, Guillemot F, Kageyama R, Gao W . (2000). Hes1 is a negative regulator of inner ear hair cell differentiation. Development 127: 4551–4560.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank T Sudo (Toray Industries Inc., Kamakura, Japan) for sharing the Hes1 antibody, and Pamela Stanley (Albert Einstein College Medicine, Bronx, NY, USA) for the TP1-Luc plasmid. We are grateful to A Velcich and L Klampfer for helpful comments. This work was supported by NCI Grants RO1 CA114265 and U54 CA100926 to LH Augenlicht, and by the Philippe Foundation.

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  1. S Guilmeau and M Flandez: These authors contributed equally to this work.

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  1. Oncology Department, Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, NY, USA

    S Guilmeau, M Flandez, J M Mariadason & L H Augenlicht

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  1. S Guilmeau
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  2. M Flandez
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  3. J M Mariadason
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  4. L H Augenlicht
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Correspondence to S Guilmeau.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Guilmeau, S., Flandez, M., Mariadason, J. et al. Heterogeneity of Jagged1 expression in human and mouse intestinal tumors: implications for targeting Notch signaling. Oncogene 29, 992–1002 (2010). https://doi.org/10.1038/onc.2009.393

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