Activin A mediates microRNA expression in prostate cancer
|dc.contributor.author||Ottley, Edward Christopher|
|dc.identifier.citation||Ottley, E. C. (2015). Activin A mediates microRNA expression in prostate cancer (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/6048||en|
|dc.description.abstract||Prostate cancer (PCa) is an increasing health issue worldwide. It is of a particular concern in New Zealand, which has one of the highest incidences of PCa globally. Broadly, PCa is composed of two main forms; latent organ-confined disease and aggressive metastatic. Treatment options for the aggressive form are limited to androgen deprivation therapy, which is only effective for a short period of time. Paired with this, the current diagnostic options available are unable to distinguish between benign prostate disease and PCa. This warrants research into more robust diagnostic and therapeutic options. Activins are members of the TGF-β superfamily and a clear association between activins and PCa has been described. Of particular importance is activin A, which has the potential to impede cancer development by promoting apoptosis and inhibiting cell proliferation. Given the potency of activin A, tight regulation is critical and one level is provided in the form of antagonists, such as follistatin. In previous years it has become clear that other factors are crucial in the regulation of cellular processes, particularly non-coding RNAs, such as microRNAs (miRNAs). MiRNAs are ~18-23 nucleotides in length and function to negatively regulate gene expression at the level of translation. While miRNAs have been shown to be important in physiological processes they have also been implicated in disease, particularly cancer. The effects of activin A on human embryonic stem cells has been investigated previously, however, the impact of activin A on miRNAs in PCa has not. This therefore represented a significant void in the literature. Hence, the overarching aim of this thesis was to investigate the effect of activin A on miRNA expression in prostate cell lines, particularly LNCaP cells, which are highly sensitive to activin A. These data herein, demonstrate the potential of activin A to modulate miRNA expression in LNCaP cells. Initially, RT-qPCR showed that 9 miRNAs demonstrated significant alterations following activin A treatment. Utilising miRPath enrichment software it was evident that these miRNAs were targeting genes contained in both canonical and non-canonical activin A signalling pathways, including, CDKN1B, PCNA, and MKI67, whose inverse expression correlated with the expression of numerous activin A-mediated miRNAs. Subsequently, following treatment with activin A and follistatin, NanoString technology revealed that 5 miRNAs significantly altered by activin A were antagonised by follistatin. Furthermore, NanoString PanCancer analysis demonstrated that MYC was highlighted in of 6 out of 13 canonical cancer pathways following activin A treatment, of which MYC was shown to contain binding sites for activin A-mediated miRNAs. MYC, therefore could be playing a central role following activin A treatment. Next-generation sequencing libraries for activin A and media control were generated for LNCaP cells and screened for the presence of novel miRNAs using miRDeep* software and identified a potentially novel miRNA which was modulated by activin A. In conclusion, for the first time, these data demonstrate a relationship between activin A, miRNA expression and downstream target genes in PCa. This thesis forms a foundation for further investigation into activin A expression levels in conjunction with the expression of miRNAs and the genes they target. These findings may provide potential targets for the diagnosis and treatment of PCa.|
|dc.publisher||University of Otago|
|dc.rights||All items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.|
|dc.title||Activin A mediates microRNA expression in prostate cancer|
|thesis.degree.name||Doctor of Philosophy|
|thesis.degree.grantor||University of Otago|
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