Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.780473
Title: Investigating small non-coding RNA regulating the hallmarks of cancer
Author: Dhawan, Andrew
ISNI:       0000 0004 7966 1150
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Abstract:
Non-coding RNA are increasingly being implicated as key regulators of the human transcriptome, and are thought to play important roles in the pathogenesis and progression of cancer. Understanding how non-coding RNA, specifically microRNA (miRNA) and circular RNA (circRNA), contribute to cancer is an area of significant clinical interest. In this work, I utilise existing large genomic datasets, generated from the Cancer Genome Atlas and Metabric projects to gain insight into the associations between coding and non-coding RNA. In the first chapter, I develop a statistical methodology (sigQC), by which the applicability of mRNA gene expression signatures to datasets and the quality of this application can be assessed. In a second chapter, I use this methodology to generate a statistical mapping from miRNA to gene signatures for the hallmarks of cancer. I show that there is a core set of miRNA statistically associated with these gene signatures, which preferentially and, in some cases, exclusively, anti-correlate across cancer types with a subset of tumour suppressor genes, such as PTEN, FAT4, and CDK12. In the next chapter, I build upon emerging knowledge of the changes to miRNA biogenesis in hypoxia, involving amplification of AGO2 and codeletion of DICER1, and determine the miRNA statistically associated both with these copy number changes and with hypoxia gene expression. In doing so, I have statistically associated miRNA which have mature form associated with poor prognosis, increased invasiveness, and metastasis. Following this, I carry out an analysis of circRNA in breast cancers, uncovering statistical evidence which may be indicative of an autoregulatory feedback mechanism associated with hypoxia gene signature expression, involving a circRNA antisense to the HSP90AB1 gene. Having identified the potential involvement of a circRNA, a species thought to function as repressors, or sponges for miRNA molecules, I characterised the possible effects of generalised miRNA sponges on the dynamics of a non-coding RNA (ncRNA) feedback loop. By analysing a system of delay differential equations in the deterministic and stochastic settings, I uncovered the range of potential dynamics that this feedback loop could exhibit. I showed that different kinetic properties for miRNA sponges gave rise to different behaviours of this network, including transient or sustained oscillations, which may have important roles in cancer and developmental biology.
Supervisor: Buffa, Francesca ; Harris, Adrian ; Scott, Jacob G. Sponsor: Clarendon Fund ; Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.780473  DOI: Not available
Keywords: Oncology ; Computational Biology
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