Hannah L. Moody
MicroRNA-31 regulates chemosensitivity in malignant pleural mesothelioma
Moody, Hannah L.; Lind, Michael J.; Maher, Stephen G.
Professor Michael Lind M.J.Lind@hull.ac.uk
Foundation Professor of Oncology/ Head of the Joint Centre for Cancer Studies
Stephen G. Maher
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.
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
|Journal Article Type||Article|
|Acceptance Date||Jul 3, 2017|
|Online Publication Date||Jul 8, 2017|
|Publication Date||Sep 15, 2017|
|Deposit Date||Aug 11, 2017|
|Publicly Available Date||Aug 11, 2017|
|Journal||Molecular therapy : nucleic acids|
|Publisher||Elsevier (Cell Press)|
|Peer Reviewed||Peer Reviewed|
|Issue||15 September 2017|
|Keywords||Malignant pleural mesothelioma; MicroRNA-31; Chemoresistance; Cisplatin; ABCB9|
Publisher Licence URL
© 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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