{"id":{"repo_id":"adelaide","oai_identifier":"oai:digital.library.adelaide.edu.au:2440/124148"},"canonical_url":"https://search.dev.ndltd.org/etd/adelaide/oai:digital.library.adelaide.edu.au:2440/124148","repository":{"repo_id":"adelaide","name":"University of Adelaide","base_url":"https://digital.library.adelaide.edu.au/server/oai/request"},"display":{"title":"The role of microRNA-194 in prostate cancer progression","abstract":"Prostate cancer is a major cause of cancer-related mortality in Australia men. Mortality is primarily due to metastasis and the development of resistance to therapy. While prostate cancer is primarily driven by the androgen receptor signalling, a number of other factors play important roles in its growth and progression. In particular, small non-coding RNA molecules called microRNAs (miRNAs) are known to be key regulators of progression in prostate cancer. Our group previously identified one specific miRNA, miR-194-5p (miR-194), as an important driver of prostate cancer metastasis; however, the molecular mechanisms by miR-194 mediates these effects is not fully understood. My PhD project aimed to identify target genes and pathways that miR-194 regulates in order to better understand its role in prostate cancer. I used cutting-edge genomic techniques and bioinformatics to identify 163 miR-194 target genes in prostate cancer. In Chapter 3, I used this data to identify a new role for miR-194 in prostate cancer. More specifically, I found that miR-194 activity was inversely correlated with androgen receptor (AR) activity in clinical samples, an observation explained mechanistically by AR-mediated repression of miR-194 expression. In concordance with these findings, miR-194 activity was significantly elevated in treatment-induced neuroendocrine prostate cancer (NEPC), an aggressive AR-independent subtype of prostate cancer. Furthermore, miR-194 can enhance transdifferentiation of epithelial LNCaP cells to neuroendocrine-like cells, a function mediated at least in part by its ability to target the FOXA1 transcription factor. Importantly, targeting miR-194 effectively inhibited the growth of aggressive models of NEPC, including patient-derived organoids. By integrating the miR-194 “targetome” with transcriptomic data, my work has provided important insights into miRNA function in cancer cells (Chapter 4). Specifically, I have found that miR-194 functions potently through canonical interactions and can mediate co-operative repression through targeting multiple sites in the same mRNA transcript. Further, I have demonstrated that miR-194 is associated with widespread non-canonical interactions that can regulate gene expression, albeit to a lesser extent than canonical sites. Finally, in Chapter 5 I have demonstrated that miR-194 has dichotomous effects on proliferation and invasion in breast and prostate cancer despite both cancers having several underlying biological similarities. Furthermore, in breast cancer I have found that miR-194 inhibits estrogen receptor expression, potentially by targeting FOXA1. Overall, my work has provided unique insights into the pathobiology of miR-194, demonstrated its role as a potential therapeutic target in aggressive AR-independent prostate cancer subtypes, and identified novel functions for miR-194 in breast cancer.","abstract_html":"Prostate cancer is a major cause of cancer-related mortality in Australia men. Mortality is primarily due to metastasis and the development of resistance to therapy. While prostate cancer is primarily driven by the androgen receptor signalling, a number of other factors play important roles in its growth and progression. In particular, small non-coding RNA molecules called microRNAs (miRNAs) are known to be key regulators of progression in prostate cancer. Our group previously identified one specific miRNA, miR-194-5p (miR-194), as an important driver of prostate cancer metastasis; however, the molecular mechanisms by miR-194 mediates these effects is not fully understood. My PhD project aimed to identify target genes and pathways that miR-194 regulates in order to better understand its role in prostate cancer. I used cutting-edge genomic techniques and bioinformatics to identify 163 miR-194 target genes in prostate cancer. In Chapter 3, I used this data to identify a new role for miR-194 in prostate cancer. More specifically, I found that miR-194 activity was inversely correlated with androgen receptor (AR) activity in clinical samples, an observation explained mechanistically by AR-mediated repression of miR-194 expression. In concordance with these findings, miR-194 activity was significantly elevated in treatment-induced neuroendocrine prostate cancer (NEPC), an aggressive AR-independent subtype of prostate cancer. Furthermore, miR-194 can enhance transdifferentiation of epithelial LNCaP cells to neuroendocrine-like cells, a function mediated at least in part by its ability to target the FOXA1 transcription factor. Importantly, targeting miR-194 effectively inhibited the growth of aggressive models of NEPC, including patient-derived organoids. By integrating the miR-194 “targetome” with transcriptomic data, my work has provided important insights into miRNA function in cancer cells (Chapter 4). Specifically, I have found that miR-194 functions potently through canonical interactions and can mediate co-operative repression through targeting multiple sites in the same mRNA transcript. Further, I have demonstrated that miR-194 is associated with widespread non-canonical interactions that can regulate gene expression, albeit to a lesser extent than canonical sites. Finally, in Chapter 5 I have demonstrated that miR-194 has dichotomous effects on proliferation and invasion in breast and prostate cancer despite both cancers having several underlying biological similarities. Furthermore, in breast cancer I have found that miR-194 inhibits estrogen receptor expression, potentially by targeting FOXA1. Overall, my work has provided unique insights into the pathobiology of miR-194, demonstrated its role as a potential therapeutic target in aggressive AR-independent prostate cancer subtypes, and identified novel functions for miR-194 in breast cancer.","abstract_has_math":false,"creators":["Fernandes, Rayzel Candida"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Seith, Luke A.","Hickey, Theresa E.","Tilley, Wayne D."],"committee_chairs":[],"committee_members":[],"year":2019,"date_issued":"2019","date_published":"2019","updated_at":"2026-07-24T00:50:36Z","subjects":["micro RNA","miR-194","prostate cancer","androgen receptor","neuroendocrine prostate cancer","breast cancer"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/2440/124148","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Seith, Luke A.","Hickey, Theresa E.","Tilley, Wayne D."]},{"key":"dc:creator","label":"Author","values":["Fernandes, Rayzel Candida"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2019"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["micro RNA","miR-194","prostate cancer","androgen receptor","neuroendocrine prostate cancer","breast cancer"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/2440/124148"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Prostate cancer is a major cause of cancer-related mortality in Australia men. Mortality is primarily due to metastasis and the development of resistance to therapy. While prostate cancer is primarily driven by the androgen receptor signalling, a number of other factors play important roles in its growth and progression. In particular, small non-coding RNA molecules called microRNAs (miRNAs) are known to be key regulators of progression in prostate cancer. Our group previously identified one specific miRNA, miR-194-5p (miR-194), as an important driver of prostate cancer metastasis; however, the molecular mechanisms by miR-194 mediates these effects is not fully understood. My PhD project aimed to identify target genes and pathways that miR-194 regulates in order to better understand its role in prostate cancer. I used cutting-edge genomic techniques and bioinformatics to identify 163 miR-194 target genes in prostate cancer. In Chapter 3, I used this data to identify a new role for miR-194 in prostate cancer. More specifically, I found that miR-194 activity was inversely correlated with androgen receptor (AR) activity in clinical samples, an observation explained mechanistically by AR-mediated repression of miR-194 expression. In concordance with these findings, miR-194 activity was significantly elevated in treatment-induced neuroendocrine prostate cancer (NEPC), an aggressive AR-independent subtype of prostate cancer. Furthermore, miR-194 can enhance transdifferentiation of epithelial LNCaP cells to neuroendocrine-like cells, a function mediated at least in part by its ability to target the FOXA1 transcription factor. Importantly, targeting miR-194 effectively inhibited the growth of aggressive models of NEPC, including patient-derived organoids. By integrating the miR-194 “targetome” with transcriptomic data, my work has provided important insights into miRNA function in cancer cells (Chapter 4). Specifically, I have found that miR-194 functions potently through canonical interactions and can mediate co-operative repression through targeting multiple sites in the same mRNA transcript. Further, I have demonstrated that miR-194 is associated with widespread non-canonical interactions that can regulate gene expression, albeit to a lesser extent than canonical sites. Finally, in Chapter 5 I have demonstrated that miR-194 has dichotomous effects on proliferation and invasion in breast and prostate cancer despite both cancers having several underlying biological similarities. Furthermore, in breast cancer I have found that miR-194 inhibits estrogen receptor expression, potentially by targeting FOXA1. Overall, my work has provided unique insights into the pathobiology of miR-194, demonstrated its role as a potential therapeutic target in aggressive AR-independent prostate cancer subtypes, and identified novel functions for miR-194 in breast cancer."]},{"key":"dc:title","label":"Title","values":["The role of microRNA-194 in prostate cancer progression"]}]}],"canonical_facts":{"dc:contributor.advisor":["Seith, Luke A.","Hickey, Theresa E.","Tilley, Wayne D."],"dc:creator":["Fernandes, Rayzel Candida"],"dc:date.issued":["2019"],"dc:description.abstract":["Prostate cancer is a major cause of cancer-related mortality in Australia men. Mortality is primarily due to metastasis and the development of resistance to therapy. While prostate cancer is primarily driven by the androgen receptor signalling, a number of other factors play important roles in its growth and progression. In particular, small non-coding RNA molecules called microRNAs (miRNAs) are known to be key regulators of progression in prostate cancer. Our group previously identified one specific miRNA, miR-194-5p (miR-194), as an important driver of prostate cancer metastasis; however, the molecular mechanisms by miR-194 mediates these effects is not fully understood. My PhD project aimed to identify target genes and pathways that miR-194 regulates in order to better understand its role in prostate cancer. I used cutting-edge genomic techniques and bioinformatics to identify 163 miR-194 target genes in prostate cancer. In Chapter 3, I used this data to identify a new role for miR-194 in prostate cancer. More specifically, I found that miR-194 activity was inversely correlated with androgen receptor (AR) activity in clinical samples, an observation explained mechanistically by AR-mediated repression of miR-194 expression. In concordance with these findings, miR-194 activity was significantly elevated in treatment-induced neuroendocrine prostate cancer (NEPC), an aggressive AR-independent subtype of prostate cancer. Furthermore, miR-194 can enhance transdifferentiation of epithelial LNCaP cells to neuroendocrine-like cells, a function mediated at least in part by its ability to target the FOXA1 transcription factor. Importantly, targeting miR-194 effectively inhibited the growth of aggressive models of NEPC, including patient-derived organoids. By integrating the miR-194 “targetome” with transcriptomic data, my work has provided important insights into miRNA function in cancer cells (Chapter 4). Specifically, I have found that miR-194 functions potently through canonical interactions and can mediate co-operative repression through targeting multiple sites in the same mRNA transcript. Further, I have demonstrated that miR-194 is associated with widespread non-canonical interactions that can regulate gene expression, albeit to a lesser extent than canonical sites. Finally, in Chapter 5 I have demonstrated that miR-194 has dichotomous effects on proliferation and invasion in breast and prostate cancer despite both cancers having several underlying biological similarities. Furthermore, in breast cancer I have found that miR-194 inhibits estrogen receptor expression, potentially by targeting FOXA1. Overall, my work has provided unique insights into the pathobiology of miR-194, demonstrated its role as a potential therapeutic target in aggressive AR-independent prostate cancer subtypes, and identified novel functions for miR-194 in breast cancer."],"dc:identifier.uri":["http://hdl.handle.net/2440/124148"],"dc:language.iso":["en"],"dc:subject":["micro RNA","miR-194","prostate cancer","androgen receptor","neuroendocrine prostate cancer","breast cancer"],"dc:title":["The role of microRNA-194 in prostate cancer progression"],"dc:type":["Thesis"]},"updated_at":"2026-07-24T00:50:36Z"}