Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Indole-3-Carbinol Promotes Goblet-Cell Differentiation Regulating Wnt and Notch Signaling Pathways AhR-Dependently

  • Park, Joo-Hung (Department of Biology, Changwon National University) ;
  • Lee, Jeong-Min (Department of Biology, Changwon National University) ;
  • Lee, Eun-Jin (Department of Biology, Changwon National University) ;
  • Hwang, Won-Bhin (Department of Biology, Changwon National University) ;
  • Kim, Da-Jeong (Department of Biology, Changwon National University)
  • Received : 2017.08.11
  • Accepted : 2018.01.08
  • Published : 2018.04.30
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Abstract

Using an in vitro model of intestinal organoids derived from intestinal crypts, we examined effects of indole-3-carbinol (I3C), a phytochemical that has anticancer and aryl hydrocarbon receptor (AhR)-activating abilities and thus is sold as a dietary supplement, on the development of intestinal organoids and investigated the underlying mechanisms. I3C inhibited the in vitro development of mouse intestinal organoids. Addition of ${\alpha}$-naphthoflavone, an AhR antagonist or AhR siRNA transfection, suppressed I3C function, suggesting that I3C-mediated interference with organoid development is AhR-dependent. I3C increased the expression of Muc2 and lysozyme, lineage-specific genes for goblet cells and Paneth cells, respectively, but inhibits the expression of IAP, a marker gene for enterocytes. In the intestines of mice treated with I3C, the number of goblet cells was reduced, but the number of Paneth cells and the depth and length of crypts and villi were not changed. I3C increased the level of active nonphosphorylated ${\beta}$-catenin, but suppressed the Notch signal. As a result, expression of Hes1, a Notch target gene and a transcriptional repressor that plays a key role in enterocyte differentiation, was reduced, whereas expression of Math1, involved in the differentiation of secretory lineages, was increased. These results provide direct evidence for the role of AhR in the regulation of the development of intestinal stem cells and indicate that such regulation is likely mediated by regulation of Wnt and Notch signals.

Keywords

References

  1. Abbott, B.D., Birnbaum, L.S., and Perdew, G.H. (1995). Developmental expression of two members of a new class of transcription factors: I. Expression of aryl hydrocarbon receptor in the C57BL/6N mouse embryo. Dev. Dyn. 204, 133-143. https://doi.org/10.1002/aja.1002040204
  2. Ahmad, A., Sakr, W.A., and Rahman, K.M. (2010). Anticancer properties of indole compounds: mechanism of apoptosis induction and role in chemotherapy. Curr Drug Targets 11, 652-666. https://doi.org/10.2174/138945010791170923
  3. Barker, N., van Es, J. H., Kuipers, J., Kujala, P., van den Born, M., Cozijnsen, M., Haegebarth, A., Korving, J., Begthel, H., Peters, P. J., et al. (2007). Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003-1007. https://doi.org/10.1038/nature06196
  4. Barker, N., van de Wetering, M., and Clevers, H. (2008). The intestinal stem cell. Genes Dev. 22, 1856-1864. https://doi.org/10.1101/gad.1674008
  5. Barouki, R., Coumoul, X., and Fernandez-Salguero, P.M. (2007). The aryl hydrocarbon receptor, more than a xenobiotic-interacting protein. FEBS Lett. 581, 3608-3615. https://doi.org/10.1016/j.febslet.2007.03.046
  6. Bjeldanes, L.F., Kim, J.Y., Grose, K.R., Bartholomew, J.C., and Bradfield, C.A. (1991). Aromatic hydrocarbon responsivenessreceptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Proc. Natl. Acad. Sci. USA 88, 9543-9547. https://doi.org/10.1073/pnas.88.21.9543
  7. Bjerknes, M., and Cheng, H. (1981). The stem-cell zone of the small intestinal epithelium. I. Evidence from Paneth cells in the adult mouse. Am. J. Anat. 160, 51-63. https://doi.org/10.1002/aja.1001600105
  8. Bray, S.J. (2006). Notch signalling: a simple pathway becomes complex. Nat. Rev. Mol. Cell Biol. 7, 678-689. https://doi.org/10.1038/nrm2009
  9. Burbach, K.M., Poland, A., and Bradfield, C.A. (1992). Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor. Proc. Natl. Acad. Sci. USA 89, 8185-8189. https://doi.org/10.1073/pnas.89.17.8185
  10. Celloto, V.R., Oliveira, A.J., Goncalves, J.E., Watanabe, C.S., Matioli, G., and Goncalves, R.A. (2012). Biosynthesis of indole-3-acetic acid by new Klebsiella oxytoca free and immobilized cells on inorganic matrices. ScientificWorldJournal 2012, 1-7.
  11. Cheng, H., and Leblond, C.P. (1974). Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. I. Columnar cell. Am. J. Anat. 141, 461-479. https://doi.org/10.1002/aja.1001410403
  12. Chmill, S., Kadow, S., Winter, M., Weighardt, H., and Esser, C. (2010). 2,3,7,8,-tetrachlorodibenzo-p-dioxin impairs stable establishment of oral tolerance in mice. Toxicol. Sci. 118, 98-107. https://doi.org/10.1093/toxsci/kfq232
  13. Coant, N., Ben Mkaddem, S., Pedruzzi, E., Guichard, C., Treton, X., Ducroc, R., Freund, J.N., Cazals-Hatem, D., Bouhnik, Y., Woerther, P.L., et al. (2010). NADPH oxidase 1 modulates WNT and NOTCH1 signaling to control the fate of proliferative progenitor cells in the colon. Mol. Cell Biol. 30, 2636-2650. https://doi.org/10.1128/MCB.01194-09
  14. Denison, M.S., and Nagy, S.R. (2003). Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Ann. Rev. Pharmacol. Toxicol. 43, 309-334. https://doi.org/10.1146/annurev.pharmtox.43.100901.135828
  15. Fre, S., Hannezo, E., Sale, S., Huyghe, M., Lafkas, D., Kissel, H., Louvi, A., Greve, J., Louvard, D., and Artavanis-Tsakonas, S. (2011). Notch lineages and activity in intestinal stem cells determined by a new set of knock-in mice. PLoS One 6, e25785. https://doi.org/10.1371/journal.pone.0025785
  16. Fre, S., Huyghe, M., Mourikis, P., Robine, S., Louvard, D., and Artavanis-Tsakonas, S. (2005). Notch signals control the fate of immature progenitor cells in the intestine. Nature 435, 964-968. https://doi.org/10.1038/nature03589
  17. Gandarillas, A., and Watt, F.M. (1997). c-Myc promotes differentiation of human epidermal stem cells. Genes Dev. 11, 2869-2882. https://doi.org/10.1101/gad.11.21.2869
  18. Hammerschmidt-Kamper, C., Biljes, D., Merches, K., Steiner, I., Daldrup, T., Bol-Schoenmakers, M., Pieters, R.H.H., and Esser, C. (2017). Indole-3-carbinol, a plant nutrient and AhR-Ligand precursor, supports oral tolerance against OVA and improves peanut allergy symptoms in mice. PLoS One 12, e0180321. https://doi.org/10.1371/journal.pone.0180321
  19. Hankinson, O. (2005). Role of coactivators in transcriptional activation by the aryl hydrocarbon receptor. Arch. Biochem. Biophys. 433, 379-386. https://doi.org/10.1016/j.abb.2004.09.031
  20. Heuberger, J., Kosel, F., Qi, J., Grossmann, K.S., Rajewsky, K., and Birchmeier, W. (2014). Shp2/MAPK signaling controls goblet/paneth cell fate decisions in the intestine. Proc. Natl. Acad. Sci. USA 111, 3472-3477. https://doi.org/10.1073/pnas.1309342111
  21. Jensen, J., Pedersen, E.E., Galante, P., Hald, J., Heller, R.S., Ishibashi, M., Kageyama, R., Guillemot, F., Serup, P., and Madsen, O.D. (2000). Control of endodermal endocrine development by Hes-1. Nat. Genet. 24, 36-44. https://doi.org/10.1038/71657
  22. Kiss, E.A., Vonarbourg, C., Kopfmann, S., Hobeika, E., Finke, D., Esser, C., and Diefenbach, A. (2011). Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science 334, 1561-1565. https://doi.org/10.1126/science.1214914
  23. Kopan, R., and Ilagan, M.X. (2009). The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137, 216-233. https://doi.org/10.1016/j.cell.2009.03.045
  24. Lasorella, A., Benezra, R., and Iavarone, A. (2014). The ID proteins: master regulators of cancer stem cells and tumour aggressiveness. Nat. Rev. Cancer 14, 77-91. https://doi.org/10.1038/nrc3638
  25. Lee, D.M., Lee, S.H., Jeong, K.T., Hwang, S.J., and Park, J.H. (2012). SDS3 interacts with ARNT in an AhR ligand-specific manner regulating expression of cKrox and S100A4 in CD4+CD8+ DPK thymocytes differentiation. Environ. Toxicol. Pharmacol. 34, 858-868. https://doi.org/10.1016/j.etap.2012.08.014
  26. Li, Y., Innocentin, S., Withers, D.R., Roberts, N.A., Gallagher, A.R., Grigorieva, E.F., Wilhelm, C., and Veldhoen, M. (2011). Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147, 629-640. https://doi.org/10.1016/j.cell.2011.09.025
  27. Li, Y., Kong, D., Ahmad, A., Bao, B., and Sarkar, F.H. (2013). Antioxidant function of isoflavone and 3,3'-diindolylmethane: are they important for cancer prevention and therapy? Antioxid. Redox. Signal. 19, 139-150. https://doi.org/10.1089/ars.2013.5233
  28. MacDonald, B.T., Tamai, K., and He, X. (2009). Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev. Cell 17, 9-26. https://doi.org/10.1016/j.devcel.2009.06.016
  29. Maruthanila, V.L., Poornima, J., and Mirunalini, S. (2014). Attenuation of carcinogenesis and the mechanism underlying by the influence of indole-3-carbinol and its metabolite 3,3'-diindolylmethane: a therapeutic marvel. Adv. Pharmacol. Sci. 2014, 832161.
  30. McManus, E.J., Sakamoto, K., Armit, L.J., Ronaldson, L., Shpiro, N., Marquez, R., and Alessi, D.R. (2005). Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis. EMBO J. 24, 1571-1583. https://doi.org/10.1038/sj.emboj.7600633
  31. Medema, J.P., and Vermeulen, L. (2011). Microenvironmental regulation of stem cells in intestinal homeostasis and cancer. Nature 474, 318-326. https://doi.org/10.1038/nature10212
  32. Mustata, R.C., Van Loy, T., Lefort, A., Libert, F., Strollo, S., Vassart, G., and Garcia, M.I. (2011). Lgr4 is required for Paneth cell differentiation and maintenance of intestinal stem cells ex vivo. EMBO Rep. 12, 558-564. https://doi.org/10.1038/embor.2011.52
  33. Nguyen, L.P., and Bradfield, C.A. (2008). The search for endogenous activators of the aryl hydrocarbon receptor. Chem. Res. Toxicol. 21, 102-116. https://doi.org/10.1021/tx7001965
  34. Ohtsuka, T., Ishibashi, M., Gradwohl, G., Nakanishi, S., Guillemot, F., and Kageyama, R. (1999). Hes1 and Hes5 as notch effectors in mammalian neuronal differentiation. EMBO J. 18, 2196-2207. https://doi.org/10.1093/emboj/18.8.2196
  35. Park, S.L., Justiniano, R., Williams, J.D., Cabello, C.M., Qiao, S., and Wondrak, G.T. (2015). The tryptophan-derived endogenous Aryl hydrocarbon receptor ligand 6-formylindolo[3,2-b]carbazole is a nanomolar UVA photosensitizer in epidermal keratinocytes. J. Invest. Dermatol. 135, 1649-1658. https://doi.org/10.1038/jid.2014.503
  36. Park, J.H., Choi, A.J., Kim, S.J., Cheong, S.W., and Jeong, S.Y. (2016). AhR activation by 6-formylindolo[3,2-b]carbazole and 2,3,7,8-tetrachlorodibenzo-p-dioxin inhibit the development of mouse intestinal epithelial cells. Environ. Toxicol. Pharmacol. 43, 44-53. https://doi.org/10.1016/j.etap.2016.02.007
  37. Perdew, G.H., and Babbs, C.F. (1991). Production of Ah receptor ligands in rat fecal suspensions containing tryptophan or indole-3-carbinol. Nutr. Cancer 16, 209-218. https://doi.org/10.1080/01635589109514159
  38. Peterson, L.W., and Artis, D. (2014). Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat. Rev. Immunol. 14, 141-153. https://doi.org/10.1038/nri3608
  39. Qiu, J., Heller, J.J., Guo, X., Chen, Z.M., Fish, K., Fu, Y.X., and Zhou, L. (2012). The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 36, 92-104. https://doi.org/10.1016/j.immuni.2011.11.011
  40. Quintana, F.J., Basso, A.S., Iglesias, A.H., Korn, T., Farez, M.F., Bettelli, E., Caccamo, M., Oukka, M., and Weiner, H.L. (2008). Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 453, 65-71. https://doi.org/10.1038/nature06880
  41. Schneider, A.J., Branam, A.M., P and eterson, R.E. (2014). Intersection of AHR and Wnt signaling in development, health, and disease. Int. J. Mol. Sci. 15, 17852-17885. https://doi.org/10.3390/ijms151017852
  42. Simon-Assmann, P., Turck, N., Sidhoum-Jenny, M., Gradwohl, G., and Kedinger, M. (2007). In vitro models of intestinal epithelial cell differentiation. Cell Biol Toxicol. 23, 241-256. https://doi.org/10.1007/s10565-006-0175-0
  43. Tung, E.K., Wong, B.Y., Yau, T.O., and Ng, I.O. (2012). Upregulation of the Wnt co-receptor LRP6 promotes hepatocarcinogenesis and enhances cell invasion. PLoS One 7, e36565. https://doi.org/10.1371/journal.pone.0036565
  44. van der Flier, L.G., and Clevers, H. (2009). Stem cells, self-renewal, and differentiation in the intestinal epithelium. Ann. Rev. Physiol. 71, 241-260. https://doi.org/10.1146/annurev.physiol.010908.163145
  45. van Es, J.H., Jay, P., Gregorieff, A., van Gijn, M.E., Jonkheer, S., Hatzis, P., Thiele, A., van den Born, M., Begthel, H., Brabletz, T., et al. (2005a). Wnt signalling induces maturation of Paneth cells in intestinal crypts. Nat. Cell Biol. 7, 381-386. https://doi.org/10.1038/ncb1240
  46. van Es, J.H., van Gijn, M.E., Riccio, O., van den Born, M., Vooijs, M., Begthel, H., Cozijnsen, M., Robine, S., Winton, D.J., Radtke, F., et al. (2005b). Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435, 959-963. https://doi.org/10.1038/nature03659
  47. Veldhoen, M., Hirota, K., Westendorf, A.M., Buer, J., Dumoutier L, Renauld, J.C., and Stockinger, B. (2008). The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106-109. https://doi.org/10.1038/nature06881
  48. Wang, H.C., Zhou, Y., and Huang, S.K. (2017). SHP-2 phosphatase controls aryl hydrocarbon receptor-mediated ER stress response in mast cells. Arch. Toxicol. 91, 1739-1748. https://doi.org/10.1007/s00204-016-1861-1
  49. Weng, J.R., Tsai, C.H., Kulp, S.K., and Chen, C.S. (2008). Indole-3-carbinol as a chemopreventive and anti-cancer agent. Cancer Lett. 262, 153-163. https://doi.org/10.1016/j.canlet.2008.01.033
  50. Wincent, E., Amini, N., Luecke, S., Glatt, H., Bergman, J., Crescenzi, C., Rannug, A., and Rannug, U. (2009). The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo[3,2-b]carbazole is present in humans. J. Biol. Chem. 284, 2690-2696. https://doi.org/10.1074/jbc.M808321200
  51. Yaktine, A.L., Harrison, G.G., and Lawrence, R.S. (2006). Reducing exposure to dioxins and related compounds through foods in the next generation. Nutr. Rev. 64, 403-409. https://doi.org/10.1111/j.1753-4887.2006.tb00225.x
  52. Yang, Q., Bermingham, N.A., Finegold, M.J., and Zoghbi, H.Y. (2001). Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science 294, 2155-2158. https://doi.org/10.1126/science.1065718
  53. Yang, L., Tang, H., Kong, Y., Xie, X., Chen, J., Song, C., Liu, X., Ye, F, Li, N., Wang, N., et al. (2015). LGR5 promotes breast cancer progression and maintains stem-like cells through activation of Wnt/${\beta}$-catenin signaling. Stem Cells 33, 2913-2924. https://doi.org/10.1002/stem.2083
  54. Zhang, N., Yantiss, R.K., Nam, H.S., Chin, Y., Zhou, X.K., Scherl, E.J., Bosworth, B.P., Reya, T., and Clevers, H. (2005). Wnt signalling in stem cells and cancer. Nature 434, 843-850. https://doi.org/10.1038/nature03319

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