118 Hepatocyte Nuclear Factor 4α (Hnf4a) Provokes Intestinal Genes in Squamous Oesophageal Cells

Colleypriest, Benjamin J.; Farrant, Mark; Griffiths, Leonard P.; Slack, Jonathan; Tosh, David

doi:10.1016/s0016-5085(13)60098-0

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“…); its induction results in intestinal marker expression in a mouse oesophageal model (Colleypriest et al . ), and it is enriched in BM (Wang et al . ).…”

Section: Discussionmentioning

confidence: 99%

“…HNF4a targets are also enriched following exposure to acidified bile, suggesting an increase in HNF4a transcriptional activity with mixed reflux. HNF4a plays a role in establishing the intestinal epithelial phenotype (Babeu et al 2009); its induction results in intestinal marker expression in a mouse oesophageal model (Colleypriest et al 2011), and it is enriched in BM (Wang et al 2009). Furthermore, there is a putative HNF4a binding site upstream of CDX2, with HNF4a activating CDX2 in HeLa cells (Benahmed et al 2008).…”

Section: Developmental Transcription Factor Targets Are Enriched By Smentioning

confidence: 99%

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Pulsatile exposure to simulated reflux leads to changes in gene expression in a 3D model of oesophageal mucosa

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Nicholls

Heath

et al. 2014

Int J Experimental Path

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Oesophageal exposure to duodenogastroesophageal refluxate is implicated in the development of Barrett's metaplasia (BM), with increased risk of progression to oesophageal adenocarcinoma. The literature proposes that reflux exposure activates NF-κB, driving the aberrant expression of intestine-specific caudal-related homeobox (CDX) genes. However, early events in the pathogenesis of BM from normal epithelium are poorly understood. To investigate this, our study subjected a 3D model of the normal human oesophageal mucosa to repeated, pulsatile exposure to specific bile components and examined changes in gene expression. Initial 2D experiments with a range of bile salts observed that taurochenodeoxycholate (TCDC) impacted upon NF-κB activation without causing cell death. Informed by this, the 3D oesophageal model was repeatedly exposed to TCDC in the presence and absence of acid, and the epithelial cells underwent gene expression profiling. We identified ~300 differentially expressed genes following each treatment, with a large and significant overlap between treatments. Enrichment analysis (Broad GSEA, DAVID and Metacore™; GeneGo Inc) identified multiple gene sets related to cell signalling, inflammation, proliferation, differentiation and cell adhesion. Specifically NF-κB activation, Wnt signalling, cell adhesion and targets for the transcription factors PTF1A and HNF4α were highlighted. Our data suggest that HNF4α isoform switching may be an early event in Barrett's pathogenesis. CDX1/2 targets were, however, not enriched, suggesting that although CDX1/2 activation reportedly plays a role in BM development, it may not be an initial event. Our findings highlight new areas for investigation in the earliest stages of BM pathogenesis of oesophageal diseases and new potential therapeutic targets.

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“…); its induction results in intestinal marker expression in a mouse oesophageal model (Colleypriest et al . ), and it is enriched in BM (Wang et al . ).…”

Section: Discussionmentioning

confidence: 99%

Section: Developmental Transcription Factor Targets Are Enriched By Smentioning

confidence: 99%

Pulsatile exposure to simulated reflux leads to changes in gene expression in a 3D model of oesophageal mucosa

Green

Nicholls

Heath

et al. 2014

Int J Experimental Path

View full text Add to dashboard Cite

show abstract

118 Hepatocyte Nuclear Factor 4α (Hnf4a) Provokes Intestinal Genes in Squamous Oesophageal Cells

Cited by 1 publication

References 0 publications

Pulsatile exposure to simulated reflux leads to changes in gene expression in a 3D model of oesophageal mucosa

Pulsatile exposure to simulated reflux leads to changes in gene expression in a 3D model of oesophageal mucosa

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