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    MicroRNA-31 Regulates Chemosensitivity in Malignant Pleural Mesothelioma

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    Publication date
    2017-09-15
    Author
    Moody, Hannah L.
    Lind, M.
    Maher, S.G.
    Keyword
    Malignant pleural mesothelioma
    microRNA-31
    Chemoresistance
    Cisplatin
    ABCB9
    Rights
    (c) 2017 The Authors. This is an Open Access article distributed under the Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/)
    Peer-Reviewed
    Yes
    
    Metadata
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    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.
    URI
    http://hdl.handle.net/10454/18034
    Version
    Published version
    Citation
    Moody HL, Lind M and Maher SG (2017) MicroRNA-31 Regulates Chemosensitivity in Malignant Pleural Mesothelioma. Molecular Therapy: Nucleic Acids. 8: 317-329.
    Link to publisher’s version
    https://doi.org/10.1016/j.omtn.2017.07.001
    Type
    Article
    Collections
    Life Sciences Publications

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