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

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• 作者：Benjamin J. Colleypriest^a ; ^b ; Zoë ; D. Burke^a ; ¹ ; Leonard P. Griffiths^a ; ^b ; ¹ ; Yu Chen^a ; ¹ ; Wei-Yuan Yu^a ; Ramiro Jover^c ; Michael Bock^d ; Leigh Biddlestone^b ; Jonathan M. Quinlan^b ; Stephen G. Ward^e ; J. Mark Farrant^b ; Jonathan M.W. Slack^a ; ^f ; David. Tosh^a ; ^{D.Tosh@bath.ac.uk}
• 关键词：Barrett's oesophagus ; HNF4α ; Hepatocyte nuclear factor 4-alpha ; Oesophageal cancer ; Metaplasia
• 刊名：Differentiation
• 出版年：2017
• 出版时间：January-February 2017
• 年：2017
• 卷：93
• 期：Complete
• 页码：39-49
• 全文大小：1815 K
• 卷排序：93

文摘

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.