The role of Cdx2 and HNF4α in Barrett’s metaplasia

Colleypriest BJ1,2, Burke ZD1, Griffiths LP1,2, Slack JMW1,3 and Tosh D1

  1. University of Bath, UK.
  2. Royal United Hospital, Bath, UK.
  3. Stem Cell Institute, University of Minnesota, USA.

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 key developmental 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. In the human biopsy samples we demonstrate the expression of both CDX2 and HNF4α. 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, in these cultures induced expression of Tff3, villin, K8 and E-cadherin. So 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.