Investigating the links between expression, function and epigenetic regulation of microRNA

Abstract

MicroRNAs (miRNAs) are master regulators of many biological processes, thus aberrant miRNA expression can contribute to the development and progression of diseases, such as prostate cancer (PCa), via key disease-related pathways, such as epithelial-mesenchymal transition(EMT). Therefore, this project investigated the expression, function and epigenetic regulation of miRNAs regarding their involvement in EMT during PCa progression. A combination of in vitro and in silico approaches were employed.

Two miRNAs, hsa-miR-21-5p (miR-21) and hsa-miR-182-5p (miR-182), were selected for investigation based on literature evidence and bioinformatic analysis of available data. A systematic review was subsequently carried out to assess the prognostic value of miR-21 in PCa. The expression profiles, biomarker potential, clinical associations and network functional enrichment of both miRNAs were examined by bioinformatic analysis using online clinical datasets. For each miRNA, a novel target gene was identified and experimentally validated in multiple PCa cell-lines. Their DNA methylation status were explored in three online datasets. The effect of TGF-β stimulation on these miRNAs was tested using glaucoma cell-lines in addition to PCa cell-lines.

Overall results revealed that miR-21 is a potential biomarker for PCa prognosis. Both miRNAs are significantly overexpressed and associated with clinicopathological characteristics in PCa. Their target networks are functionally associated with EMT. Two novel EMT-related genes,FERMT2 and MITF, were validated as target of miR-21 and miR-182 respectively. Preliminary results suggest that their expressions may be influenced by DNA methylation and TGF-β stimulation.

In summary, this thesis presents original data evidencing that miR-21 and miR-182 have valuable biomarker potential, and they are likely involved in PCa progression by contributing to EMT. Results presented warrant further investigations into the interaction, functional and regulatory network of these miRNAs with the long-term view to identifying the most effective biomarkers and treatment targets that can be translated into clinical use for human healthcare.

Date of Award	Apr 2023
Original language	English
Sponsors	Department for the Economy
Supervisor	Declan McKenna (Supervisor), Colm Walsh (Supervisor) & Colin Willoughby (Supervisor)