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

Benjamin J. Colleypriest, Zoë D. Burke, Leonard P. Griffiths, Yu Chen, Wei-Yuan Yu, Ramiro Jover, Michael Bock, Leigh Biddlestone, Jonathan M. Quinlan, Stephen G. Ward, J. Mark Farrant, Jonathan M W Slack, David Tosh

Research output: Contribution to journalArticle

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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.

LanguageEnglish
Pages39-49
Number of pages11
JournalDifferentiation
Volume93
DOIs
StatusPublished - 1 Jan 2017

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Barrett Esophagus
Metaplasia
Organ Culture Techniques
Epithelium
Phenotype
Genes
Biopsy
Cadherins
Infection
Esophagus
Adenocarcinoma
Transcription Factors
Polymerase Chain Reaction

Keywords

  • Barrett's oesophagus
  • Hepatocyte nuclear factor 4-alpha
  • HNF4α
  • Metaplasia
  • Oesophageal cancer

Cite this

Hnf4α is a key gene that can generate columnar metaplasia in oesophageal epithelium. / Colleypriest, Benjamin J.; Burke, Zoë D.; Griffiths, Leonard P.; Chen, Yu; Yu, Wei-Yuan; Jover, Ramiro; Bock, Michael; Biddlestone, Leigh; Quinlan, Jonathan M.; Ward, Stephen G.; Mark Farrant, J.; Slack, Jonathan M W; Tosh, David.

In: Differentiation, Vol. 93, 01.01.2017, p. 39-49.

Research output: Contribution to journalArticle

Colleypriest, BJ, Burke, ZD, Griffiths, LP, Chen, Y, Yu, W-Y, Jover, R, Bock, M, Biddlestone, L, Quinlan, JM, Ward, SG, Mark Farrant, J, Slack, JMW & Tosh, D 2017, 'Hnf4α is a key gene that can generate columnar metaplasia in oesophageal epithelium' Differentiation, vol 93, pp. 39-49. DOI: 10.1016/j.diff.2016.11.001
Colleypriest, Benjamin J. ; Burke, Zoë D. ; Griffiths, Leonard P. ; Chen, Yu ; Yu, Wei-Yuan ; Jover, Ramiro ; Bock, Michael ; Biddlestone, Leigh ; Quinlan, Jonathan M. ; Ward, Stephen G. ; Mark Farrant, J. ; Slack, Jonathan M W ; Tosh, David. / Hnf4α is a key gene that can generate columnar metaplasia in oesophageal epithelium. In: Differentiation. 2017 ; Vol. 93. pp. 39-49
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