6533b83afe1ef96bd12a71fd

RESEARCH PRODUCT

Hnf4α is a key gene that can generate columnar metaplasia in oesophageal epithelium

Jonathan M. QuinlanZoë D. BurkeYu ChenRamiro JoverLeonard P. GriffithsDavid ToshStephen G. WardJ. Mark FarrantM BockJonathan M.w. SlackLeigh BiddlestoneWei-yuan YuBenjamin J. Colleypriest

subject

0301 basic medicineMalePathologyCancer ResearchEsophageal NeoplasmsBiopsyEpitheliumMice0302 clinical medicineMetaplasiaCDX2 Transcription FactorCDX2CàncerOesophageal cancerAnatomyNeoplasm ProteinsBarrett's oesophagusGene Expression Regulation Neoplasticmedicine.anatomical_structureHepatocyte Nuclear Factor 4Loricrin/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being030211 gastroenterology & hepatologymedicine.symptomVillinHepatocyte nuclear factor 4-alphaAdultmedicine.medical_specialtyStratified squamous epitheliumBiologyAdenocarcinomaOrgan cultureArticle03 medical and health sciencesBarrett EsophagusEsophagusOrgan Culture TechniquesSDG 3 - Good Health and Well-beingmedicineAnimalsHumansMolecular BiologyHNF4αMetaplasiaHistologiaCell BiologyEpitheliumdigestive system diseases030104 developmental biologybiology.proteinEctopic expressionDevelopmental Biology

description

AbstractBarrett'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.

yearjournalcountryeditionlanguage
2017-01-01
10.1016/j.diff.2016.11.001http://hdl.handle.net/10550/65810