title: A pSMAD/CDX2 complex is essential for the intestinalization of epithelial metaplasia.
abstract: The molecular mechanisms leading to epithelial metaplasias are poorly understood. Barrett's esophagus is a premalignant metaplastic change of the esophageal epithelium into columnar epithelium, occurring in patients suffering from gastroesophageal reflux disease. Mechanisms behind the development of the intestinal subtype, which is associated with the highest cancer risk, are unclear. In humans, it has been suggested that a nonspecialized columnar metaplasia precedes the development of intestinal metaplasia. Here, we propose that a complex made up of at least two factors needs to be activated simultaneously to drive the expression of intestinal type of genes. Using unique animal models and robust in vitro assays, we show that the nonspecialized columnar metaplasia is a precursor of intestinal metaplasia and that pSMAD/CDX2 interaction is essential for the switch toward an intestinal phenotype.
authors.affiliation: Centre for Experimental & Molecular Medicine, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands; Department of Gastroenterology & Hepatology, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.
authors.forename: Luigi
authors.initials: L
authors.lastname: Mari
authors.affiliation: Centre for Experimental & Molecular Medicine, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands; Department of Gastroenterology & Hepatology, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands; Section of Hematology and Clinical Immunology, Department of Internal and Experimental Medicine, Ospedale S. Maria della Misericordia, University of Perugia, 06156 Perugia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Milano
authors.affiliation: Centre for Experimental & Molecular Medicine, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands; Department of Gastroenterology & Hepatology, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.
authors.forename: Kaushal
authors.initials: K
authors.lastname: Parikh
authors.affiliation: Centre for Experimental & Molecular Medicine, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands; Department of Gastroenterology & Hepatology, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.
authors.forename: Danielle
authors.initials: D
authors.lastname: Straub
authors.affiliation: Core facility Cellular Imaging/LCAM-AMC, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.
authors.forename: Vincent
authors.initials: V
authors.lastname: Everts
authors.affiliation: Core facility Cellular Imaging/LCAM-AMC, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.
authors.forename: Kees K
authors.initials: KK
authors.lastname: Hoeben
authors.affiliation: Department of Gastroenterology & Hepatology, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: Fockens
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55902, USA.
authors.forename: Navtej S
authors.initials: NS
authors.lastname: Buttar
authors.affiliation: Centre for Experimental & Molecular Medicine, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands; Department of Gastroenterology & Hepatology, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands. Electronic address: k.k.krishnadath@amc.uva.nl.
authors.forename: Kausilia K
authors.initials: KK
authors.lastname: Krishnadath
mesh_terms: D000818:Animals; D001471:Barrett Esophagus / Q000378:metabolism* / Q000473:pathology; D055415:Bone Morphogenetic Protein 4 / Q000096:biosynthesis; D000071616:CDX2 Transcription Factor; D002454:Cell Differentiation; D002460:Cell Line; D004195:Disease Models, Animal; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008679:Metaplasia / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D051785:Smad Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C525809:BMP4 protein, human; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; C487514:Cdx2 protein, mouse; D018398:Homeodomain Proteins; D051785:Smad Proteins; D014157:Transcription Factors