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Title: MicroRNA implications in chemotherapy-induced cardiac toxicity
Author: Roca-Alonso, Laura
ISNI:       0000 0004 5348 554X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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The use of anthracyclines such as doxorubicin (DOX) has improved mortality and morbidity in cancer patients, yet associated risks of cardiomyopathy have limited their clinical application. DOX-associated cardiotoxicity typically progresses to heart failure (HF). The knowledge of the mechanisms underlying DOX-related cardiac dysfunction is currently limited, hampering the development of cardioprotective strategies. MicroRNAs (miRNAs) are gene expression regulators that play potent roles in both cardiovascular disease and cancer. We wished to investigate DOX-induced changes in cardiac miRNA expression and the potential alteration of cellular processes downstream. Myocardial miRNA profiling was performed after DOX injury, either via acute administration to cardiomyocytes in vitro or chronic exposure in vivo, and compared to miRNA profiles from infarcted hearts. We identified an overlapping down-regulation of several members of the miR-30 family. Subsequent experimental validation of a bioinformatically predicted subset of target genes allowed us to confirm four novel miR-30 targets: β1- and β2-adrenoceptors (β1AR, β2AR), Gi alpha 2 (Giα-2) and the pro-apoptotic gene BNIP3L, all of which are essential in cardiomyocytes. The implications of the β-adrenergic pathway in HF are extensively described. Importantly, we show a preferential βAR inhibition by miR-30, having a β-blocker like effect. Additionally, we demonstrate that high miR-30 levels are protective against DOX insults and correlate with lower reactive oxygen species generation in cardiac cultures. Upstream of these mechanisms, we describe the transcription factor GATA-6 to be involved in mediating DOX-induced miR-30 down-regulation. Finally, when assessing the implications of miR-30 in breast cancer, we observed an inverse correlation between miR-30 expression levels and breast cancer cell migration in vitro. Moreover, bioinformatic analyses revealed reduced miR-30 levels in breast cancer patients. Taken together, our findings encourage a potential translational use for miR-30 as an early biomarker as well as a therapeutic strategy, combining a cardioprotective action with pleiotropic anti-cancer effects.
Supervisor: Stebbing, Justin; Castellano, Leandro Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available