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Hnf4? 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 HNF4? in the conversion using primary organ cultures. Biopsy samples from cases of human Barrett's metaplasia were analysed for the presence of CDX2 and HNF4?. A new organ culture system for adult murine oesophagus is described. Using this, Cdx2 and HNF4? 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 HNF4? in human biopsy samples. Our oesophageal organ culture system expressed markers characteristic of the normal SSQE: p63, K14, K4 and loricrin. Ectopic expression of HNF4?, but not of Cdx2 induced expression of Tff3, villin, K8 and E-cadherin. HNF4? 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 HNF4? 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.

SUBMITTER: Colleypriest BJ

PROVIDER: S-EPMC5293356 | biostudies-literature | 2017 Jan - Feb

REPOSITORIES: biostudies-literature

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

Colleypriest Benjamin J BJ Burke Zoë D ZD Griffiths Leonard P LP Chen Yu Y Yu Wei-Yuan WY Jover Ramiro R Bock Michael M Biddlestone Leigh L Quinlan Jonathan M JM Ward Stephen G SG Mark Farrant J J Slack Jonathan M W JMW Tosh David D

Differentiation; research in biological diversity 20161119

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 ...[more]

PMID: 27875772

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Project description:Background and aimsThe mechanism of transformation to intestinal metaplasia in Barrett's oesophagus has not been clarified. We investigated the effects of various bile acids on expression of the caudal related homeobox gene Cdx2 in cultured oesophageal squamous epithelial cells. In addition, morphological and histochemical changes in squamous cells to intestinal epithelial cells were studied in response to bile acid induced expression of Cdx2.MethodsA rat model of Barrett's oesophagus was created by anastomosing the oesophagus and jejunum, and Cdx2 expression was investigated by immunohistochemistry. Also, the response of various bile acids on Cdx2 gene expression was studied in the human colon epithelial cell lines Caco-2 and HT-29, as well as in cultured rat oesophageal squamous epithelial cells using a Cdx2 promoter luciferase assay. In addition, primary cultured oesophageal squamous epithelial cells were transfected with Cdx2 expression vectors and their possible transformation to intestinal-type epithelial cells was investigated.ResultsOesophagojejunal anastomoses formed intestinal goblet cell metaplasia in rat oesophagus specimens and metaplastic epithelia strongly expressed Cdx2. When the effects of 11 types of bile acids on Cdx2 gene expression were examined, only cholic acid (CA) and dehydrocholic acid dose dependently increased Cdx2 promoter activity and Cdx2 protein production in Caco-2 and HT-29 cells, and cultured rat oesophageal keratinocytes. Results from mutation analysis of Cdx2 promoter suggested that two nuclear factor kappaB (NFkappaB) binding sites were responsible for the bile acid induced activation of the Cdx2 promoter. When bile acids were measured in oesophageal refluxate of rats with experimental Barrett's oesophagus, the concentration of CA was found to be consistent with the experimental dose that augmented Cdx2 expression in vitro. Furthermore, transfection of the Cdx2 expression vector in cultured rat oesophageal keratinocytes induced production of intestinal-type mucin, MUC2, in cells that expressed Cdx2.ConclusionsWe found that CA activates Cdx2 promoter via NFkappaB and stimulates production of Cdx2 protein in oesophageal keratinocytes with production of intestinal-type mucin. This may be one of the mechanisms of metaplasia in Barrett's oesophagus.

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Hnf4? is a key gene that can generate columnar metaplasia in oesophageal epithelium.

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

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