Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597456
Title: Retinoid signalling in Barrett's metaplasia and carcinogenesis
Author: Chang, C.-L.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2006
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Abstract:
The aim of this research is to investigate whether there is any evidence for a role of RA in the development of Barrett’s metaplasia and subsequent carcinogenesis. First, an ex vivo organ culture system was established in which columnar metaplasia could be induced by exogenous all-trans RA (ATRA) from a squamous tissue, and conversely, squamous metaplasia could be induced from a Barrett’s tissue. Molecular characterisation of these induced-phenotypes was performed with a variety of markers. In addition, the factors that may have contributed to the activation of endogenous RA signalling in vivo were explored. The results demonstrated that bile acid, lithocholic acid (LCA) and Cdx2 over-expression can increase RA bioactivity. On the other hand, a relative depletion of RA activity was noted in Barrett’s cancerous cells comparing to non-dysplastic Barrett’s cells. I went on to demonstrate that reduced RA may be due to the increased expression of a RA catabolising enzyme – CYP26A1. Using serial functional assays, CYP26A1 gene over-expression was demonstrated to be able to enhance Barrett’s cell proliferation, invasion, and drive the cells into an undifferentiated state. The pattern of gene expression was in keeping with the functional changes in that there was induction of genes involved in cell survival and reduced expression of cell death genes. In addition, there was induction of the oncogenes c-Myc and EGFR (epidermal growth factor receptor). The role of CYP26a1 gene activation in Barrett’s carcinogenesis introduces the possibility of a wider role for this gene in cancer. It is hoped that works arsing from this thesis can help further understanding of Barrett’s oesophagus and associated adenocarcinoma so that future developments can be made in its treatment and prevention.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.597456  DOI: Not available
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