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MicroRNA-31 regulates chemosensitivity in malignant pleural mesothelioma

Moody, Hannah L.; Lind, Michael J.; Maher, Stephen G.

Authors

Professor Michael Lind M.J.Lind@hull.ac.uk
Foundation Professor of Oncology/ Head of the Joint Centre for Cancer Studies

Stephen G. Maher

Abstract

Malignant pleural mesothelioma (MPM) is associated with an extremely poor prognosis, and most patients initially are 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 many MPM tumors. Based on previous findings in a variety of other cancers, we hypothesized that miR-31 alters chemosensitivity and that miR-31 reconstitution may influence sensitivity to chemotherapeutics in MPM. Reintroduction of miR-31 into miR-31 null NCI-H2452 cells significantly enhanced clonogenic resistance to cisplatin and carboplatin. Although miR-31 re-expression increased chemoresistance, paradoxically, a higher relative intracellular accumulation of platinum was detected. This was coupled to a significantly decreased intranuclear concentration of platinum. 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 that miR-31 promotes chemoresistance largely via an ABCB9-independent mechanism. Overall, our data suggest that miR-31 loss from MPM tumors promotes chemosensitivity and may be prognostically beneficial in the context of therapeutic sensitivity.

Journal Article Type Article
Publication Date Sep 15, 2017
Journal Molecular therapy : nucleic acids
Print ISSN 2162-2531
Electronic ISSN 2162-2531
Publisher Elsevier (Cell Press)
Peer Reviewed Peer Reviewed
Volume 8
Issue 15 September 2017
Pages 317-329
Institution Citation Moody, H. L., Lind, M. J., & Maher, S. G. (2017). MicroRNA-31 regulates chemosensitivity in malignant pleural mesothelioma. Molecular Therapy - Nucleic Acids, 8(15 September 2017), 317-329. https://doi.org/10.1016/j.omtn.2017.07.001
DOI https://doi.org/10.1016/j.omtn.2017.07.001
Keywords Malignant pleural mesothelioma; MicroRNA-31; Chemoresistance; Cisplatin; ABCB9
Publisher URL http://www.sciencedirect.com/science/article/pii/S2162253117302111

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Copyright Statement
© 2017 The Authors

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).




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