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Regulation of HPGD and SLCO2A1 in Colorectal Cancer Development

Papagrigoriou, Spyridon (2018) Regulation of HPGD and SLCO2A1 in Colorectal Cancer Development. PhD thesis, University of Leeds.

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Abstract

A wide range of lipid mediators are synthesised from Polyunsaturated Fatty Acids. These mediators regulate inflammation and many other processes in the human body, and perturbation of their signalling can contribute to the survival and proliferation of cancer cells. Prostaglandin E2 has the most diverse range of functions amongst the prostaglandins and other lipid mediators, and increased PGE2 signalling has been associated with promoting tumour growth and survival by a number of mechanisms. NSAIDs target the synthesis side of the prostaglandin pathway through PTGS2, but only recently has the importance of the degradation component, involving the enzyme HPGD and prostaglandin transporter SLCO2A1 been discovered. Although a number of publications have shown that HPGD is downregulated in colorectal cancer, in addition to other malignancies, the mechanisms by which this takes place remain unclear. Only a few studies have indicated a comparable role for SLCO2A1, and the potential for these two genes to be co-regulated. Therefore, understanding how these two genes are regulated could reveal the mechanisms by which their expression is lost, and potentially how they could be upregulated to complement the action of NSAIDs when used prophylactically, or as an adjunct to chemotherapy. HPGD and SLCO2A1 expression was characterised, and the genes’ transcriptional start sites identified using two colorectal cancer cell lines. This information was used to design and carry out a promoter deletion series, which revealed the importance of the proximal 364 bp SLCO2A1 promoter region in driving transcription. Further analysis of this region revealed a possible role for the intestinal and colonic epithelium-specific transcription factor CDX2 for driving SLCO2A1 expression. Further experiments provided evidence to suggest that the TGF-β pathway, which is known to drive HPGD expression, may also co-regulate SLCO2A1.

Item Type: Thesis (PhD)
Academic Units: The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Genetics (Leeds)
The University of Leeds > Faculty of Medicine and Health (Leeds)
The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds)
The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds)
Identification Number/EthosID: uk.bl.ethos.778616
Depositing User: Mr Spyridon Papagrigoriou
Date Deposited: 29 May 2019 11:09
Last Modified: 18 Feb 2020 12:50
URI: http://etheses.whiterose.ac.uk/id/eprint/23898

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