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THE ROLE OF PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA (PPARα) IN THE EFFECT OF PIROXICAM ON COLON CANCER KAREN MARIE McCARTNEY BSc. (Hons), MSc. Thesis submitted to the University of Nottingham for the degree of Doctor of Philosophy April 2015 Abstract Studies with APCMin/+ mice and APCMin/+ PPARα-/- mice were undertaken to investigate whether polyp development in the mouse gut was mediated by PPARα. Additionally, the effect of piroxicam treatment dependency on PPARα was assessed. Results showed the number of polyps in the colon was significantly higher in APCMin/+ PPARα-/- mice than in APCMin/+ mice, whilst in the small bowel the difference was not significant. Analysis of gene expression in the colon with Affymetrix® microarrays demonstrated the largest source of variation was between tumour and normal tissue. Deletion of PPARα had little effect on gene expression in normal tissue but appeared to have more effect in tumour tissue. Ingenuity pathway analysis of these data showed the top biological processes were growth & proliferation and colorectal cancer. Collectively, these data may indicate that deletion of PPARα exacerbates the existing APCMin/+ mutation to promote tumorigenesis in the colon. 95 genes from Affymetrix® microarray data were selected for further analysis on Taqman® low density arrays. There was good correlation of expression levels between the two array types. Expression data of two genes proved particularly interesting; Onecut homeobox 2 (Onecut2) and Apolipoprotein B DNA dC dU - editing enzyme, catalytic polypeptide 3 (Apobec3). Onecut2 was highly up-regulated in tumour tissue. Apobec3 was up-regulated in APCMin/+ PPARα-/- mice only; suggesting expression was mediated via PPARα. There was a striking increase in survival accompanied by a marked reduction in small intestinal polyp numbers in mice of either genotype that received piroxicam. Taqman® low density array analysis of the same 95 genes as previously showed similar expression levels in piroxicam-treated APCMin/+ mice and APCMin/+ PPARα-/- mice. Taken together, these data indicated that the effect of piroxicam treatment was not mediated via PPARα. i Declaration The work in this thesis was performed entirely by myself (unless otherwise stated) and in no way forms part of any other thesis. The work was carried out at the Nottingham Digestive Diseases Centre (NDDC), Queens Medical Centre, University Hospital, Nottingham, and the School of Biomedical Sciences, University of Nottingham, under the joint supervision of Professor C.J. Hawkey and Dr A.J. Bennett. Karen Marie McCartney ii Publications & Presentations Publications Gut 2011, 60 A115-A116 Gastroenterology 2010 138 (5) S502 Gastroenterology 2009, 136 (5) A618-A619 Gastroenterology 2009, 136 (5) A752-A753 Gastroenterology 2008, 134 (4) A304 Presentations British Society of Gastroenterology 14/03/11 – 17/03/11 Birmingham NCC *Poster submitted ‘Substantial chemo-preventative effect of piroxicam in Min mice independent of peroxisome proliferator activated receptor alpha’ *Awarded poster of distinction United European Gastroenterology Week 23/10/10 – 27/10/10 Barcelona, Spain Poster submitted ‘Substantial chemo-preventative effect of piroxicam in Min mice independent of peroxisome proliferator activated receptor alpha’ Digestive Diseases Week 1/05/10 – 5/05/10 New Orleans, LA Poster submitted ‘Increased longevity in polyp-bearing mice treated with piroxicam’ European Association of Cancer Research Symposium (EACR) 3/07/09 Nottingham Poster submitted ‘The role of PPAR alpha in the effects of NSAIDs upon colon cancer’ iii Abbreviations used in this thesis AA Arachidonic acid APC Adenomatous polyposis coli ASPA Animals (Scientific Procedures) Act 1986 BLAST Basic local alignment search tool BMSU Biomedical Science Unit Cox Cyclooxygenase Cyp Cytochrome P450 FAP Familial adenomatous polyposis IPA Ingenuity pathway analysis IPKB Ingenuity Pathway Knowledge Base Lox Lipoxygenase Min Multiple intestinal neoplasia NCBI National Centre for Biotechnology Information NSAIDs Non-steroidal anti-inflammatory drugs PPAR Peroxisome proliferator activated receptor PPRE Peroxisome proliferator response element RT Q PCR Real Time Quantitative Polymerase Chain Reaction UTR Untranslated region iv Acknowledgements I would like to dedicate this research to my four children, Emma, Lisa, Zoe and Luke, and to the memory of their dad, Les. I would like to thank my two supervisors, Professor Christopher Hawkey – Chris, and Dr Andrew Bennett – Andy, for their insight, support, help and encouragement during my research and personal difficulties. I would also like to acknowledge and thank the Medical Research Council, and the School of Clinical Sciences, University of Nottingham, for funding this research. I would like to say thank you to my children for championing their mum throughout the years of my study. Thank you also to Richard, for his unswerving support - and the odd glass or two of wine! To my dad, I would like to say – I have done it! When the going got tough, I kept going. Thank you for having faith in me. A big thank you to all FRAME lab members especially Elke Gottschalg for her ‘listening ear’ and support, and Monika Owen and Nicki De Vivo, for their assistance and constructive advice in the lab. Thank you to all of the staff in the Biomedical Support Unit for their help with my mouse studies, especially Mark Trussell and Neil Yates. And thank you to Dr Emma King, Denise Christie and Ian Ward in the Advanced Microscopy Unit, for help and instruction with microscopes and staining techniques. I would like to say a special thank you for the support and compassion shown to me by the late Professor Sue Watson. Lastly, but by no means least, to my friends and colleagues in the Nottingham Digestive Diseases Centre, and especially Diane Stevenson, Jen Dumbleton and Rosemary Dainty, I would like to say thank you for being there to chat about life, music, theatre etc. etc. - anything but ‘the PhD!’ v Table of Contents Abstract ……………………………………………………………………… i Declaration ………..………………………………………………………… ii Publications & Presentations ……………………………………………... iii Abbreviations used in this thesis …………………………………………. iv Acknowledgements .………………………………………………………... v Table of Contents ………………………………………………………….. vi List of Figures …………………………………………………………........ xi List of Tables ………………………………………………………………. xv 1 Introduction..................................................................................... 1 1.1 Function, structure & histology of the small bowel & colon ...... 2 1.2 Early detection & screening for colon cancer .......................... 4 1.3 Pathogenesis of colon cancer ................................................. 5 1.4 Adenomatosis polyposis coli gene (APC gene) & the Min mouse model ..................................................................................... 8 1.4.1 Min mice as a model for Familial Adenomatous Polyposis (FAP) & colon cancer ..................................................................... 9 1.5 Metabolism of Arachidonic Acid ............................................ 11 1.6 Eicosanoid pathways in colorectal cancer development & progression ...................................................................................... 16 1.6.1 Cyclooxygenase pathway ................................................ 16 1.6.2 Lipoxygenase pathway .................................................... 18 1.6.3 Cytochrome P-450 pathway ............................................. 19 1.7 Mechanism of action of Cyclooxygenase-2 ........................... 19 1.7.1 Apoptosis ......................................................................... 19 1.7.2 Angiogenesis ................................................................... 20 1.7.3 Metastasis ........................................................................ 21 1.7.4 Immune effects ................................................................ 21 vi 1.7.5 Resolution of inflammation ............................................... 22 1.8 Cyclooxygenase inhibitors as cancer treatment & prevention 22 1.8.1 Aspirin .............................................................................. 22 1.8.2 Non-selective non-steroidal anti-inflammatory drugs (NSAIDs) ...................................................................................... 23 1.8.3 Selective cyclooxygenase 2 (Cox-2) inhibitors ................. 24 1.8.4 PPARα as a target for eicosanoids .................................. 24 1.8.5 PPARs as a target for NSAIDs......................................... 25 1.9 Peroxisome proliferator activated receptors (PPARs) ........... 25 1.10 PPARs – Role in Cancer and Inflammation ........................... 31 1.10.1 PPAR alpha (PPARα) ................................................... 31 1.10.2 PPAR beta/delta (PPARβ/δ) ......................................... 33 1.10.3 PPAR gamma (PPAR γ) ............................................... 35 1.10.4 Pan & dual-PPAR agonists ........................................... 36 1.11 Hypothesis ............................................................................ 37 1.12 Aims and Objectives .............................................................. 37 2 Materials ....................................................................................... 39 2.1 Reagents ............................................................................... 39 2.2 Protocols for preparation of working solutions & buffers ....... 41 3 The role of PPARα in malignant pathology
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