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Title: Investigation of resolvin E1 as a metabolite of eicosapentaenoic acid with anti-colorectal cancer activity
Author: Hutchinson, John Michael
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2016
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Eicosapentaenoic acid (EPA) is an omega (ω)-3 polyunsaturated fatty acid (PUFA) found at high levels in oily fish such as salmon and mackerel. EPA has been shown to have anti-colorectal cancer (CRC) effects in two clinical studies where it was shown to reduce polyp burden in familial adenomatous polyposis (FAP) patients, and possibly improve overall survival in patients following liver resection for CRC liver metastases. At present, it is unknown how EPA exerts its anti-CRC effects. Resolvin E1 (RvE1) is a lipid with anti-inflammatory and pro-resolving activities derived from EPA. RvE1 biosynthesis requires three enzymes; aspirin acetylated cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) and leukotriene A4 hydrolase (LTA4H). RvE1 has been shown to mediate its anti-inflammatory effects through two different G-protein coupled receptors, ChemR23 and BLT1. The hypothesis was that RvE1 synthesised within CRC could induce CRC cell apoptosis through either or both ChemR23 and BLT1 receptor signaling. ChemR23 and BLT1 protein were found to be expressed by human CRC clinical samples. ChemR23 and BLT1 were expressed at lower levels in histologically normal colorectal epithelium when compared to CRC, a relationship also seen with the associated stroma. No RvE1 mediated effect on CRC survival or apoptosis was identified on ChemR23 expressing human CRC cell lines in vitro. There was no BLT1 expression by human CRC cells in vitro. Human polymorphonuclear leukocytes (PMNs) treated directly with 18- hydroxyeicosapentaenoic acid (18-HEPE) generated RvE1. In vitro CRC cells and macrophages alone and in a transcellular synthesis model failed to produce RvE1. In conclusion, ChemR23 and BLT1 receptors were found to be expressed by human CRC clinical samples. RvE1 was not synthesised by a CRC model in vitro. The candidate identified no in vitro RvE1 biological activity. Further research could look to establish whether RvE1 can be detected in human CRC samples.
Supervisor: Hull, Mark A. ; Nicolaou, Anna ; Volpato, Milene ; Loadman, Paul Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available