MicroRNA-31 regulates chemosensitivity in malignant pleural mesothelioma

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

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.

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

• 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
• Print ISSN: 2162-2531
• Publisher: Cell Press
• Peer Reviewed: Peer Reviewed
• Volume: 8
• Issue: 15 September 2017
• Pages: 317-329
• DOI: https://doi.org/10.1016/j.omtn.2017.07.001
• Keywords: Malignant pleural mesothelioma; MicroRNA-31; Chemoresistance; Cisplatin; ABCB9
• Public URL: https://hull-repository.worktribe.com/output/454015
• Publisher URL: http://www.sciencedirect.com/science/article/pii/S2162253117302111
• Contract Date: Aug 11, 2017