miR-191 promotes radiation resistance of prostate cancer through interaction with RXRA

Jessica Ray, Charles Haughey, Christianne Hoey, Jouhyun Jeon, Ross Murphy, Lara Dura-Perez, Nuala McCabe, Michelle Downes, Suneil Jain, Paul C Boutros, Ian G Mills, Stanley K Liu

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Abstract

Radiation therapy is a common treatment for prostate cancer, however recurrence remains a problem. MicroRNA expression is altered in prostate cancer and may promote therapy resistance. Through bioinformatic analyses of TCGA and CPC-GENE patient cohorts, we identified higher miR-191 expression in tumor versus normal tissue, and increased expression in higher Gleason scores. In vitro and in vivo experiments demonstrated that miR-191 overexpression promotes radiation survival, and contributes to a more aggressive phenotype. Retinoid X receptor alpha, RXRA, was discovered to be a novel target of miR-191, and knockdown recapitulated radioresistance. Furthermore, treatment of prostate cancer cells with the RXRA agonist 9-cis-retinoic acid restored radiosensitivity. Supporting this relationship, patients with high miR-191 and low RXRA abundance experienced quicker biochemical recurrence. Reduced RXRA translated to a higher risk of distant failure after radiotherapy. Notably, this miR-191/RXRA interaction was conserved in a novel primary cell line derived from radiorecurrent prostate cancer. Together, our findings demonstrate that miR-191 promotes prostate cancer survival after radiotherapy, and highlights retinoids as a potential option to improve radiotherapy response.

Original languageEnglish
JournalCancer Letters
Early online date23 Dec 2019
DOIs
Publication statusEarly online date - 23 Dec 2019

Bibliographical note

Copyright © 2019. Published by Elsevier B.V.

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    Ray, J., Haughey, C., Hoey, C., Jeon, J., Murphy, R., Dura-Perez, L., McCabe, N., Downes, M., Jain, S., Boutros, P. C., Mills, I. G., & Liu, S. K. (2019). miR-191 promotes radiation resistance of prostate cancer through interaction with RXRA. Cancer Letters. https://doi.org/10.1016/j.canlet.2019.12.025