Abstract
CDX2 is a homeobox transcription factor that works as a master gene in intestinal differentiation, both in the colon and in aberrant locations such as intestinal metaplasia (IM) of the stomach. Transgenic mice with Cdx2 expression in the stomach develop IM and Cdx2+/− mice develop hamartomatous polyps in the colon presenting gastric differentiation. We previously observed regulation of CDX2 by the BMP/SMAD pathway in the gastric context. Here, we hypothesized that juvenile polyps, which are hamartomatous polyps caused by mutations in members of the BMP/SMAD pathway, might recapitulate the gastric differentiation observed in Cdx2+/− mice due to SMAD4 and CDX2 downregulation. We characterized SMAD4 and CDX2 expression in a series of 18 solitary juvenile polyps and 2 polyps from juvenile polyposis (JP) patients, one with a germline SMAD4 mutation and one with a germline BMPRIA mutation, as well as the expression of an intestinal differentiation marker, MUC2 (by immunohistochemistry and in situ hybridization), and gastric differentiation markers, MUC5AC and MUC6 (by immunohistochemistry). We observed that juvenile polyps have a heterogeneous expression of CDX2, MUC2 and SMAD4, with negative areas, and 15 of the 18 solitary polyps and the JP case with SMAD4 mutation exhibit de novo expression of MUC5AC but not MUC6. In conclusion, juvenile polyps have gastric transdifferentiation associated with downregulation of CDX2 and SMAD4, lending support to the role of the BMP/SMAD pathway in CDX2 regulation.
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References
Almeida R, Silva E, Santos-Silva F, Silberg DG, Wang J, De Bolós C, David L (2003) Expression of intestine-specific transcription factors, CDX1 and CDX2, in intestinal metaplasia and gastric carcinomas. J Pathol 199:36–40
Attisano L, Wrana JL (2002) Signal transduction by the TGF-beta superfamily. Science 296:1646–1647
Barros R, Pereira B, Duluc I, Azevedo M, Mendes N, Camilo V, Jacobs R, Paulo P, Santos-Silva F, van Seuningen I, van den Brink G, David L, Freund JN, Almeida R (2008) Key elements of the BMP/SMAD pathway co-localize with CDX2 in intestinal metaplasia and regulate CDX2 expression in human gastric cell lines. J Pathol 215:411–420
Bartman AE, Sanderson SJ, Ewing SL, Niehans GA, Wiehr CL, Evans MK, Ho SB (1999) Aberrant expression of MUC5AC and MUC6 gastric mucin genes in colorectal polyps. Int J Cancer 80:210–218
Beck F, Chawengsaksophak K, Waring P, Playford RJ, Furness JB (1999) Reprogramming of intestinal differentiation and intercalary regeneration in CDX2 mutant mice. Proc Natl Acad Sci USA 96:7318–7323
Biemer-Huttmann A-E, Walsh MD, McGuckin MA, Simms LA, Young J, Leggett BA, Jass JR (1999) Immunohistochemical staining patterns of MUC1, MUC2, MUC4, and MUC5AC mucins in hyperplastic polyps, serrated adenomas, and traditional adenomas of the colorectum. J Histochem Cytochem 47:1039–1047
Chawengsaksophak K, James R, Hammond VE, Kontgen F, Beck F (1997) Homeosis and intestinal tumours in CDX2 mutant mice. Nature 386:84–87
Howe JR, Roth S, Ringold JC, Summers RW, Järvinen HJ, Sistonen P, Tomlinson IP, Houlston RS, Bevan S, Mitros FA, Stone EM, Aaltonen LA (1998) Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 280:1086–1088
Howe JR, Bair JL, Sayed MG, Anderson ME, Mitros FA, Petersen GM, Velculescu VE, Traverso G, Vogelstein B (2001) Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet 28:184–187
Jass JR (1999) Serrated adenoma and colorectal carcinoma. J Pathol 187:499–502
Koike M, Inada K, Nakanishi H, Matsuura A, Nakamura S, Tatematsu M (2003) Cellular differentiation status of epithelial polyps of the colorectum: the gastric foveolar cell-type in hyperplastic polyps. Histopathology 42:357–364
López-Ferrer A, de Bolós C, Barranco C, Garrido M, Isern J, Carlstedt I, Reis CA, Torrado J, Real FX (2000) Role of fucosyltransferases in the association between apomucin and Lewis antigen expression in normal and malignant gastric epithelium. Gut 47:349–356
Merg A, Howe JR (2004) Genetic conditions associated with intestinal juvenile polyps. Am J Med Genet 129C:44–55
Mesquita P, Jonckheere N, Almeida R, Ducourouble MP, Serpa J, Silva E, Pigny P, Silva FS, Reis C, Silberg D, Van Seuningen I, David L (2003) Human Muc2 mucin gene is transcriptionally regulated by Cdx homeodomain proteins in gastrointestinal carcinoma cell lines. J Biol Chem 278:51549–51556
Mesquita P, Almeida R, Lunet N, Reis CA, Silva LF, Serpa J, Van Seuningen I, Barros H, David L (2006) Metaplasia—a transdifferentiation process that facilitates cancer development: the model of gastric intestinal metaplasia. Crit Rev Oncog 12:3–26
Mochizuka A, Uehara T, Nakamura T, Kobayashi Y, Ota H (2007) Hyperplastic polyps and sessile serrated ‘adenomas’ of the colon and rectum display gastric pyloric differentiation. Histochem Cell Biol 128:445–455
Mutoh H, Hakamata Y, Sato K, Eda A, Yanaka I, Honda S, Osawa H, Kaneko Y, Sugano K (2002) Conversion of gastric mucosa to intestinal metaplasia in CDX2-expressing transgenic mice. Biochem Biophys Res Commun 294:470–479
Reis CA, David L, Nielsen PA, Clausen H, Mirgorodskaya K, Roepstorff P, Sobrinho-Simões M (1997) Immunohistochemical study of MUC5AC expression in human gastric carcinomas using a novel monoclonal antibody. Int J Cancer 74:112–121
Reis CA, Sørensen T, Mandel U, David L, Mirgorodskaya E, Roepstorff P, Kihlberg J, Hansen JE, Clausen H (1998) Development and characterization of an antibody directed to an alpha-N-acetyl-D-galactosamine glycosylated MUC2 peptide. Glycoconj J 15:51–62
Reis CA, David L, Correa P, Carneiro F, de Bolós C, Garcia E, Mandel U, Clausen H, Sobrinho-Simões M (1999) Intestinal metaplasia of human stomach displays distinct patterns of mucin (MUC1, MUC2, MUC5AC, and MUC6) expression. Cancer Res 59:1003–1007
Silberg DG, Swain GP, Suh ER, Traber PG (2000) CDX1 and CDX2 expression during intestinal development. Gastroenterology 119:961–971
Silberg DG, Sullivan J, Kahn E, Swain GP, Moffet J, Sackett SD, Kaestner KH (2002) CDX2 ectopic expression induces gastric intestinal metaplasia in transgenic mice. Gastroenterology 122:689–696
Silva E, Teixeira A, David L, Carneiro F, Reis CA, Sobrinho-Simões J, Serpa J, Veerman E, Bolscher J, Sobrinho-Simões M (2002) Mucins as key molecules for the classification of intestinal metaplasia of the stomach. Virchows Arch 440:311–317
Tamai Y, Nakajima R, Ishikawa T, Takaku K, Seldin MF, Taketo MM (1999) Colonic hamartoma development by anomalous duplication in Cdx2 knockout mice. Cancer Res 59:2965–2970
Woodford-Richens KL, Halford S, Rowan A, Bevan S, Aaltonen LA, Wasan H, Bicknell D, Bodmer WF, Houlston RS (2001) CDX2 mutations do not account for juvenile polyposis or Peutz-Jeghers syndrome and occur infrequently in sporadic colorectal cancers. Br J Cancer 84:1314–1316
Yamamoto H, Bai YQ, Yuasa Y (2003) Homeodomain protein CDX2 regulates goblet-specific MUC2 gene expression. Biochem Biophys Res Commun 300:813–818
Yao T, Kouzuki T, Kajiwara M, Matsui N, Oya M, Tsuneyoshi M (1999) “Serrated” adenoma of the colorectum, with reference to its gastric differentiation and its malignant potential. J Pathol 187:511–517
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Supported by Fundação para a Ciência e Tecnologia, Programa Operacional Ciência, Tecnologia e Inovação do Quadro Comunitário de Apoio III (Project POCTI/SAU-OBS/55840/2004, Project PTDC/SAU-OBD/64490/2006) and the European Funding FEDER.
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Barros, R., Mendes, N., Howe, J.R. et al. Juvenile polyps have gastric differentiation with MUC5AC expression and downregulation of CDX2 and SMAD4. Histochem Cell Biol 131, 765–772 (2009). https://doi.org/10.1007/s00418-009-0579-z
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DOI: https://doi.org/10.1007/s00418-009-0579-z