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Final Copy 2019 01 23 Noun This electronic thesis or dissertation has been downloaded from Explore Bristol Research, http://research-information.bristol.ac.uk Author: Nounu, Aayah Title: The use of aspirin for primary and secondary prevention of colorectal cancer General rights Access to the thesis is subject to the Creative Commons Attribution - NonCommercial-No Derivatives 4.0 International Public License. A copy of this may be found at https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode This license sets out your rights and the restrictions that apply to your access to the thesis so it is important you read this before proceeding. Take down policy Some pages of this thesis may have been removed for copyright restrictions prior to having it been deposited in Explore Bristol Research. However, if you have discovered material within the thesis that you consider to be unlawful e.g. breaches of copyright (either yours or that of a third party) or any other law, including but not limited to those relating to patent, trademark, confidentiality, data protection, obscenity, defamation, libel, then please contact [email protected] and include the following information in your message: •Your contact details •Bibliographic details for the item, including a URL •An outline nature of the complaint Your claim will be investigated and, where appropriate, the item in question will be removed from public view as soon as possible. The use of aspirin for primary and secondary prevention of colorectal cancer Aayah Ghassan Nounu A dissertation submitted to the University of Bristol in accordance with the requirements for award of the degree of Doctor of Philosophy in the Faculty of Life Sciences School of Cellular and Molecular Medicine September 2018 Word Count: 75,837 Abstract Colorectal cancer (CRC) is the third most common cancer worldwide. Observational studies and randomised controlled trials for vascular events have shown aspirin as a possible chemopreventative agent in CRC. Aspirin is a well-established inhibitor of the (COX)/(PGE2) signalling pathway. However, an aspirin derivative (NCX-4016) that does not inhibit COX activity was reported to have a better chemopreventative effect in a mouse model of colon cancer implicating other unknown aspirin anti- cancer effects. More recently aspirin has been reported to induce post-transcriptional modifications, specifically, protein and histone acetylation. The aim of this PhD thesis was to investigate the effect of short-term and long-term aspirin exposure in colorectal adenoma cells (RG/C2) by looking at the regulation of cell growth as well as changes in DNA methylation, gene and protein expression. Mendelian randomisation (MR) was used to assess whether variations in aspirin metabolite levels are associated with risk of CRC. Through combining multiple ‘omics, short-term aspirin was not found to regulate genome-wide DNA methylation but was implicated in regulating specific gene expression e.g. suppressing STMN1. This led to a reduction in cell migration, which may partly explain the anti-metastatic function of aspirin. Conversely, cells exposed long-term to aspirin (≥18 weeks) were less responsive to aspirin’s growth inhibition. Long-term treatment resulted in a genome-wide effect on DNA methylation, highlighting a previously unreported role for aspirin in epigenetic regulation. Finally, the MR approach showed a possible association between aspirin metabolism and cancer risk, complementing other epidemiological evidence with regards to aspirin use and cancer risk. For the first time, combining population-based and laboratory-based methods have identified possible new mechanisms of aspirin’s action. Genetic variants may help inform the effect of aspirin use on CRC risk and epigenetic modifications from long-term use could help identify patients who become less responsive to the drug. Acknowledgements Firstly, I would like to thank both of my supervisors, Professor Ann Williams and Professor Caroline Relton. I would like to thank Ann specifically for always asking me questions that have allowed me to truly understand my work, for always being supportive and inspiring me to think of new directions to take in research. I would also like to thank Caroline for her guidance, without which this research would not have been possible. I would also like to thank the Medical Research Council for funding my PhD. Thank you to all the kind collaborators- most specifically the GECCO consortium (in particular, Professor Ulrike Peters and Dr. Yi Lin) as well as the Twins UK registry (in particular, Miss Genevieve Lachance and Victoria Vazquez) for allowing me to use their data in order to carry out my analyses. I also acknowledge that this work would not have been possible without the data from the UK Biobank consortium. Furthermore, I recognise that the analysis of the 3D cell growth in this thesis would not have been possible without the help and microscopes from the Wolfson Bioimaging Facility. I am grateful for the help and guidance from many individuals, specifically: Dr. Gemma Sharp, Dr. Kaitlin Wade, Dr. Philip Haycock, Dr. Ed Mountjoy, Dr. Louise Millard, Dr. Anna Guyatt, Dr. Alex Greenhough and Tracey Collard. I would also like to thank everyone from both offices who have always made me feel welcome, have provided intellectual conversations and distractions when needed. Finally, I would like to thank all my family members for always encouraging me and allowing me to complete this PhD. I am grateful for having wonderful extended family members (my grandparents, aunts, uncles and cousins) for their limitless love and pride. I specifically would like to thank my sister who listened to my endless rants when things were tough, my parents who were always patient and helped whenever they could and my nieces and nephews for their constant joy who showed me the care-free and innocent side of life. V VI Author declarations Comments on the entire thesis were received from my supervisors, Professor Ann Williams and Professor Caroline Relton. I declare that the work in this dissertation was carried out in accordance with the requirements of the University's Regulations and Code of Practice for Research Degree Programmes and that it has not been submitted for any other academic award. Except where indicated by specific reference in the text, the work is the candidate's own work. Work done in collaboration with, or with the assistance of, others, is indicated as such. Any views expressed in the dissertation are those of the author. SIGNED: ............................................................. DATE:......................... VII VIII Table of contents Abstract .................................................................................................................................................. III Acknowledgements ................................................................................................................................. V Author declarations .............................................................................................................................. VII Table of contents ................................................................................................................................... IX List of tables ....................................................................................................................................... XVIII List of figures ........................................................................................................................................ XXI List of abbreviations ........................................................................................................................... XXVI Chapter 1 Introduction ........................................................................................................................ 1 1.1 Thesis overview ....................................................................................................................... 1 1.1.1 Overview ......................................................................................................................... 1 1.1.2 Importance of an inter-disciplinary approach ................................................................ 1 1.1.3 Aims and objectives ........................................................................................................ 2 1.1.4 Publications and presentations ....................................................................................... 3 1.1.5 Contributions .................................................................................................................. 3 1.2 An introduction to colorectal cancer ...................................................................................... 5 1.2.1 What is colorectal cancer? .............................................................................................. 5 1.2.2 Incidence and mortality patterns .................................................................................... 5 1.2.3 Factors that increase risk of colorectal cancer ............................................................... 6 1.2.4 Colorectal cancer diagnosis ............................................................................................ 7 1.3 Molecular aspects of colorectal cancer .................................................................................. 7 1.3.1 Colonic crypt structure ...................................................................................................
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