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Terron Canedo, Nuria (2017) Mirnas in Equine Sarcoids: Identification and Profiling of Mirnas in Equine Fibroblasts and BPV-1 Transformed Equine Fibroblasts

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Terron Canedo, Nuria (2017) Mirnas in Equine Sarcoids: Identification and Profiling of Mirnas in Equine Fibroblasts and BPV-1 Transformed Equine Fibroblasts Terron Canedo, Nuria (2017) miRNAs in equine sarcoids: Identification and profiling of miRNAs in equine fibroblasts and BPV-1 transformed equine fibroblasts. PhD thesis. https://theses.gla.ac.uk/8130/ Copyright and moral rights for this work are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This work cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Enlighten: Theses https://theses.gla.ac.uk/ [email protected] Title Page miRNAs in equine sarcoids: Identification and profiling of miRNAs in equine fibroblasts and BPV- 1 transformed equine fibroblasts Dr Nuria Terrón Canedo September 2016 This thesis is submitted to the University of Glasgow in accordance with the requirements for the degree of Doctor in Philosophy in the School of Veterinary Medicine. © Nuria Terrón Canedo Author’s declaration: I declare that the work carried out in this thesis is original and it was carried out by either myself or with the appropriate acknowledgements. Exceptions to this have been the miRCURY LNA™ microRNA Array 7th Gen (performed by an external company, Exiqon A/S, Vedbeck, Denmark), high throughput sequencing (performed by Miss Julie Galbraith at Glasgow Polyomics, University of Glasgow) and several parts of the bioinformatic analysis such as set-up of the miRDeep 2.0. pipeline and creation of scripts for data analysis of high throughput sequencing (performed by Dr. Willie Weir, University of Glasgow). The work contained in this thesis has not been presented for the award of a degree in any other university and it was carried out in the University of Glasgow under the co-supervision of Prof. L. Nasir and Dr. C. Britton. Nuria Terron Canedo September 2016 ii Acknowledgments I would like to thank my supervisors Prof Lubna Nasir and Dr Collette Britton for their help and guidance in the different parts of this project. I would also like to thank them for giving me both support in the lab and outside of the lab, when sometimes it was most needed. I would like to express my eternal gratitude to The Horserace Betting Levy Board (HBLB) and The James Herriot Scholarship Fund for the financial support, without which this project would have never happened. I would also like to thank Dr Lesley Nicolson and Dr William Weir for their contribution to the project. Special thanks to Dr William Weir for his invaluable advice on the thesis as well as on my future career. I would like to thank Miss Lizzie Gault, Dr Alan Winter, Dr Idoia Busnadiego, Mr Andrew Stevenson, Miss Natalie Hutchinson and of course my office mates Dr Adam Bell and Dr Elspeth Waugh for sharing their experience in numerous laboratory techniques that were completely new to me at the start of my PhD and became my ‘bread-and-butter’. Thanks to Dr Marco Duz for his friendship and support as a PhD sufferer and for all the de-stress therapy sessions in the form of dog walks. Huge thanks to my family, who have been incredibly supportive throughout my career and studies. Particularly I’d like to thank my mum, who has always believed in me, has encouraged me to be a curious mind and has taught me the lesson that knowledge and education are the best gifts you can ever give to a daughter. Thanks to my granny, who I believe I get the stubbornness and perseverance from, that allowed me to put the effort and hard-work during this PhD. (Spanish translation: Quisiera expresar mi enorme gratitud a mi familia, que siempre me han dado su apoyo incondicional a lo largo de las etapas tan diversas de mi carrera y estudios. En particular, me gustaria darle las gracias a mi madre, que siempre ha creido en mi, ha estimulado my curiosidad me ha enseñado que el conocimiento y la educación son los mejores regalos que se le pueden dar a una hija. Gracias a mi abuela, de quien creo que he heredado la cabezonería y perserverancia, que me han permitido poner el esfuerzo y horas de trabajo durante este doctorado). Last, but not least, big thanks to my all of my friends here in Glasgow and to all of those far away from Glasgow, who all have contributed to help me to become who I am, and who have made the journey of my PhD one of the best experiences in my life. iii Abstract Introduction: Equine sarcoids (ES) are fibroblastic cutaneous tumours, affecting members of the Equidae family (horses, donkeys, zebras), hybrids (mules) and other ungulates (tapirs and giraffes) (Marti et al., 1993; Reid et al., 1994; Knottenbelt et al., 1995; Nel et al., 2006; Valentine, 2006; Kidney & Berrocal, 2008; van Dyk et al., 2009; van Dyk et al., 2011; Schaffer et al., 2013). This debilitating disease has a prevalence of 5.6% in the British equestrian population and it is a major welfare concern in less developed countries (Ayele et al., 2007; NEHS, 2015). Age (younger horses), genetic predisposition (presence of equine leucocyte antigens class I A3 and class II B1; regions of the equine genome in chromosomes 20, 22, 23, 25 with microsatellite markers, single nucleotide polymorphisms or deletions) and breed (Quarter horse and Thoroughbred) have been identified as risk factors (Lazary et al., 1985; Brostrom et al., 1988; Mohammed et al., 1992; Marti et al., 1993; Wobeser et al., 2010; Jandova et al., 2012; Bugno-Poniewierska et al., 2016; Staiger et al., 2016). Diagnosis and treatment are challenging due to the variable clinical presentation (six clinical types), inconsistent histopathological findings and gaps in the understanding of the aetiology (Martens et al., 2000; Knottenbelt, 2005b; Taylor & Haldorson, 2013). Bovine papillomavirus type 1 and 2 (BPV-1/-2) are intrinsically linked to the development of ES. Episomal viral genomes (from 2 to over 100 copies per cell) as well as expression of the viral oncoprotein E5, E6 and E7 have been found in clinical lesions in several studies (Amtmann et al., 1980; Angelos et al., 1991; Nasir & Reid, 1999; Carr et al., 2001b; Chambers et al., 2003b; Ambros, 2004; Bogaert et al., 2007; Yuan et al., 2007b; Borzachiello et al., 2008; Nasir & Campo, 2008; Haralambus et al., 2010; Brandt et al., 2011b; Nasir & Brandt, 2013; Wilson et al., 2013). Activation of the platelet-derived growth factor receptor (PDGF-R) signaling pathway and the intracellular retention of major histocompatibility complex (MHC) class I, both driven by the BPV-1/-2 E5 oncoprotein, are the most studied cellular events in tumoural transformation in equine sarcoids (Petti et al., 1991; Ashrafi et al., 2002; Borzacchiello et al., 2006; Borzachiello et al., 2008; Marchetti et al., 2009; Altamura et al., 2013). Other recognised effects of BPV-1/-2 oncoproteins in ES are activation of p38 mitogen-activated protein kinases (p38-MAPK) (Yuan et al., 2011c), intracellular mislocation of tumour suppressor p53 (Yuan et al., 2008a), activation of p600, a member of the retinoblastoma family (Corteggio et al., 2011), downregulation of iv toll-like receptor 4 (TLR4) (Yuan et al., 2010a) and increased expression of forkhead box protein 3 (FOXP3). However, to date, the mechanisms by which the virus activates or inhibits these pathways are still poorly understood. It has been shown that in human papillomavirus (HPV) induced cancer, multiple oncogenic pathways are regulated by microRNAs (miRNAs), which are small non-coding RNAs and essential regulators at a cellular level (Gómez-Gómez et al., 2013; Honegger et al., 2015). The aberrant expression of miRNAs found in high-risk HPVs-infected cells (HR-HPV) and cervical cancer samples has contributed to the understanding of the mechanisms by which the virus initiates and perpetuates malignant transformation. Dysregulation of miRNAs (miR-106b, miR-145, miR- 15/16 cluster, miR-196a, miR-21, miR-23b and miR-92 amongst other miRNAs) has been attributed to the presence of the HPV oncoproteins E6 and E7 (Lajer et al., 2012; Ben et al., 2015; Honegger et al., 2015). Currently in the official database of miRNAs, miRBase 20.0 (www.mirbase.org) there are 711 annotated equine miRNA precursors, encoding 690 mature miRNAs, of which more than half are predicted sequences (359) (Zhou et al., 2009) and the rest have been verified in one equine testicular sample with the use of high throughput sequencing (HTS) (331 sequences) (Platt et al., 2014). Nonetheless, other studies attempted to describe miRNAs in the horse using HTS in equine semen, bone, cartilage, colon, liver and muscle (Das et al., 2013; Desjardin et al., 2014; Kim et al., 2014) although these are not included in the miRBase 20.0. Aims: The goals of the present study were to produce a detailed catalogue of mature sequences expressed in equine normal fibroblast cells (equine primary fibroblasts) and study the differential expression of miRNAs in equine sarcoids using an in vitro model previously developed at the University of Glasgow (Yuan et al., 2008a). Materials and methods: RNA was extracted from three cell lines from an equine in vitro sarcoid model: normal equine fibroblasts (EqPalFs); cells transformed with the BPV-1 genome, EqPalF-BPV-1 cells referred to as S6-2 cells; and equine tumoural fibroblasts, named EqSO4bs (Yuan et al., 2008b). miRNAs contained in the RNA fraction were assessed using miRNA microarray (EqPalF vs S6-2 cells), high throughput sequencing (HTS) (EqPalF, EqSO4b and S6-2 cells) and real-time reverse transcription polymerase chain reaction (qRT-PCR).
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