Barrett’s metaplasia (BM) is the condition whereby the stratified squamous epithelium at the lower end of oesophagus is replaced by intestinal-like columnar epithelium. BM is associated with chronic cell injury caused by acid and bile salts refluxing from the stomach (so-called Gastro-oesophageal reflux disease (GORD). BM is important clinically as it is the only known precursor to oesophageal adenocarcinoma. Metaplasia is associated with the aberrant expression of key (master switch) transcription factor(s). It is therefore possible that intestinal transcription factors such as those involved in regulation of intestinal gene expression may be involved in the development of BM. In addition, the development of BM may be linked to exogenous factors such as acid, bile salts and inflammatory mediators, which leads to an inflammatory response and the premalignant condition. Therefore, the aims of the current project are three-fold to investigate (i) the role of HNF4α in the development of BM, (ii) the role of HNF1α, CDX2, FOXA2 and PDX1 in the development of BM and (iii) the effects of exogenous factors involved in the inflammatory response and the Wnt and Notch pathways on HNF4a and CDX2 expression in the development of BM. The data showed that ectopic HNF4α, CDX2 or HNF1α expression induces intestinal gene expression in the human normal oesophageal epithelial HET1A cells, but FOXA2 or PDX1 ectopic expression did not provoke intestinal gene expression. Furthermore, ectopic HNF4α expression in mouse oesophageal epithelial explants induced the squamous-to-columnar cell type conversion as well as VILLIN protein expression. These results suggest that ectopic expression of HNF4α, CDX2 and HNF1α might be involved in the initiation of BM. Finally, exogenous factors involved in the inflammatory and the Wnt and Notch pathways treatment failed to induce intestinal gene expression in the HET1A cells, but further studies such as extending the treatment time and the use of the 3D organotypic models or animal models could be tested.
|Date of Award||13 Nov 2014|
|Supervisor||David Tosh (Supervisor) & Stephen Ward (Supervisor)|