title: Hnf4α is a key gene that can generate columnar metaplasia in oesophageal epithelium.
abstract: Barrett's metaplasia is the only known morphological precursor to oesophageal adenocarcinoma and is characterized by replacement of stratified squamous epithelium by columnar epithelium. The cell of origin is uncertain and the molecular mechanisms responsible for the change in cellular phenotype are poorly understood. We therefore explored the role of two transcription factors, Cdx2 and HNF4α in the conversion using primary organ cultures. Biopsy samples from cases of human Barrett's metaplasia were analysed for the presence of CDX2 and HNF4α. A new organ culture system for adult murine oesophagus is described. Using this, Cdx2 and HNF4α were ectopically expressed by adenoviral infection. The phenotype following infection was determined by a combination of PCR, immunohistochemical and morphological analyses. We demonstrate the expression of CDX2 and HNF4α in human biopsy samples. Our oesophageal organ culture system expressed markers characteristic of the normal SSQE: p63, K14, K4 and loricrin. Ectopic expression of HNF4α, but not of Cdx2 induced expression of Tff3, villin, K8 and E-cadherin. HNF4α is sufficient to induce a columnar-like phenotype in adult mouse oesophageal epithelium and is present in the human condition. These data suggest that induction of HNF4α is a key early step in the formation of Barrett's metaplasia and are consistent with an origin of Barrett's metaplasia from the oesophageal epithelium.
authors.affiliation: Centre for Regenerative Medicine, Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK; Department of Gastroenterology, Royal United Hospital, Combe Park, Bath BA1 3NG, UK.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Colleypriest
authors.affiliation: Centre for Regenerative Medicine, Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Zoë D
authors.initials: ZD
authors.lastname: Burke
authors.affiliation: Centre for Regenerative Medicine, Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK; Department of Gastroenterology, Royal United Hospital, Combe Park, Bath BA1 3NG, UK.
authors.forename: Leonard P
authors.initials: LP
authors.lastname: Griffiths
authors.affiliation: Centre for Regenerative Medicine, Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Centre for Regenerative Medicine, Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Wei-Yuan
authors.initials: WY
authors.lastname: Yu
authors.affiliation: Unidad Mixta Hepatologia Experimental & CIBERehd, Departamento de Bioquimica y Biologia Molecular, Universidad de Valencia, Spain.
authors.forename: Ramiro
authors.initials: R
authors.lastname: Jover
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bock
authors.affiliation: Department of Gastroenterology, Royal United Hospital, Combe Park, Bath BA1 3NG, UK.
authors.forename: Leigh
authors.initials: L
authors.lastname: Biddlestone
authors.affiliation: Department of Gastroenterology, Royal United Hospital, Combe Park, Bath BA1 3NG, UK.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Quinlan
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Ward
authors.affiliation: Department of Gastroenterology, Royal United Hospital, Combe Park, Bath BA1 3NG, UK.
authors.forename: J
authors.initials: J
authors.lastname: Mark Farrant
authors.affiliation: Centre for Regenerative Medicine, Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK; Stem Cell Institute, University of Minnesota, Minneapolis 55455, USA.
authors.forename: Jonathan M W
authors.initials: JMW
authors.lastname: Slack
authors.affiliation: Centre for Regenerative Medicine, Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK. Electronic address: D.Tosh@bath.ac.uk.
authors.forename: David
authors.initials: D
authors.lastname: Tosh
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000818:Animals; D001471:Barrett Esophagus / Q000235:genetics* / Q000473:pathology; D001706:Biopsy; D000071616:CDX2 Transcription Factor / Q000235:genetics*; D004848:Epithelium / Q000473:pathology; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D004947:Esophagus / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009924:Organ Culture Techniques
chemical_list: D000071616:CDX2 Transcription Factor; C487514:Cdx2 protein, mouse; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; D009363:Neoplasm Proteins
keywords: Barrett's oesophagus; HNF4α; Hepatocyte nuclear factor 4-alpha; Metaplasia; Oesophageal cancer