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Type: Theses
Title: MicroRNA mediated gene regulation in cancer
Author: Wang, Qingqing
Issue Date: 2017
School/Discipline: Adelaide Medical School
Abstract: Cancer, as the second cause of death worldwide, requires further understanding of its mechanism to improve patient survival and quality of life. MicroRNAs are important regulators of translation and play major roles in normal cellular functions as well as cancer pathobiology. The broad aim of my study was to provide new insight into microRNA-mediated gene regulation in cancer. Although miRNAs account for the posttranscriptional regulation of more than 60% of human protein-coding genes, this work is mainly focused on two molecular pathways: the p53 signalling pathway and the androgen receptor signalling pathway, each of which have been shown to be strongly connected to tumorigenesis. p53, a transcription factor that participates in multiple cellular functions, is considered the most important tumour suppressor and is mutated in ~50% of cancers. Previous evidence suggests that post-transcriptional deregulation of p53 by microRNAs contributes to tumorigenesis, tumour progression and therapeutic resistance. We found that the microRNA miR-766 was aberrantly expressed in breast cancer, and that overexpression of miR-766 caused accumulation of wild-type p53 protein in multiple cancer cell lines. Supporting its role in the p53 signalling pathway, miR-766 decreased cell proliferation and colony formation in several cancer cell lines, and cell cycle analyses revealed that miR-766 causes G2 arrest. At a mechanistic level, we demonstrate that miR- 766 enhances p53 signalling by directly targeting MDM4, an oncogene and negative regulator of p53. Analysis of clinical genomic data from multiple cancer types supports the relevance of miR-766 in p53 signalling. Collectively, our study demonstrates that miR-766 can function as a novel tumour suppressor by enhancing p53 signalling. Moreover, we have reported miR-9 as a novel miRNA that specifically downregulates the expression of misssense p53 R248Q and R273H in multiple cell lines, while the wild-type p53 is upregulated and other p53 mutations are unaffected. We also identified a potential binding site within TP53 ORF. A few potential mechanisms behind this unique observation are discussed. This part of my work provides novel evidence in the miRNA-mediated mutant p53 regulation and discusses the weakness of current miRNA target study. Androgen receptor (AR) is a transcription factor that is the key driver of prostate cancer growth and progression. As such, AR and its downstream pathways are a critical target for prostate cancer treatment. MiRNAs participate in the regulation of these pathways by targeting AR itself or downstream genes. In our study, we identified miR-375 as a direct negative regulator of androgen receptor and its signalling pathways. Overexpression of miR-375 results in down-regulation of AR protein and mRNA levels and AR target genes FKBP51 and KLK3, accompanied by growth inhibition of prostate cancer cells. Over-expression of AR rescued the effect of miR-375 over expression. Interestingly, AR binds the promoter region of the MIR375 gene and upregulates its expression. Thus, my work identifies a new feedback loop that balances the endogenous level of AR and miR-375 in prostate cells. Overall, this work provides further understanding of how miRNAs regulate important gene pathways in different cancers.
Advisor: Callen, David Frederick
Selth, Luke Ashton
Dissertation Note: Thesis (Ph.D.) (Research by Publication) -- University of Adelaide, Adelaide Medical School, 2017.
Keywords: MicroRNA
gene regulation
Research by Publication
Provenance: This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at:
DOI: 10.25909/5ba1f2ba145f7
Appears in Collections:Research Theses

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