Investigating the role of microRNA-31 as a modulator of chemosensitivity in malignant leural mesothelioma

Moody, Hannah Louise

Medicine
September 2016

Thesis or dissertation


Rights
© 2016 Hannah Louise Moody. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright holder.
Abstract

Malignant pleural mesothelioma (MPM) is associated with an extremely poor prognosis and the majority of patients are initially or rapidly become unresponsive to platinum-based chemotherapy. MicroRNA-31 (miR-31) is encoded on a genomic fragile site, 9p21.3, which is reportedly lost in approximately half of MPM tumours, and its prognostic value is currently ambiguous. Based on previous findings in a variety of other cancers, it was hypothesised that miR-31 loss confers chemoresistance and that miR-31 reconstitution may enhance sensitivity to chemotherapeutics in MPM. Surprisingly, reintroduction of miR-31 into epithelioid miR-31-null NCI-H2452 cells significantly enhanced clonogenic resistance to cisplatin and carboplatin. Conversely, suppression of endogenous miR-31 in P31 epithelioid cells significantly increased chemosensitivity. Interestingly, while miR-31 overexpression increased resistance to platinum-containing therapeutics, paradoxically, a higher relative intracellular concentration of platinum was observed versus controls. While the expression of the drug influx transporter CTR1 was increased upon miR-31 re-expression, a significantly decreased intranuclear concentration of platinum was observed, with associated reduction in DNA damage, potentially explaining the increase in cisplatin accumulation but decreased chemosensitivity. The converse relationship was demonstrated in P31 cells upon endogenous miR-31 suppression, further suggesting a mechanism underpinning resistance that involves altered nuclear transport. Linked with a downregulation of OCT1, a bipotential transcriptional regulator with multiple miR-31 target binding sites, we subsequently identified an indirect miR-31-mediated upregulation of ABCB9, a transporter associated with drug accumulation in lysosomes, and increased uptake of platinum to lysosomes. However, when overexpressed directly, ABCB9 promoted cellular chemosensitivity, suggesting the miR-31 promotes chemoresistance largely via an ABCB9-independent mechanism. Overall, these data suggest that miR-31 loss from MPM tumours does not promote chemoresistance in MPM, and may be prognostically beneficial in the context of therapeutic sensitivity. As such, endogenous miR-31 suppression may actually enhance sensitivity to platinum-based treatment in patients with MPM.

Publisher
Hull York Medical School, The University of Hull and University of York
Supervisor
Lind, Michael; Mahler, Stephen
Sponsor (Organisation)
University of Hull; Hull York Medical School
Qualification level
Doctoral
Qualification name
PhD
Language
English
Extent
4 MB
Identifier
hull:15140
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