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Cancer Lett. 2019 Dec 23;473:107-117. doi: 10.1016/j.canlet.2019.12.025. [Epub ahead of print]

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

Author information

1
Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Canada.
2
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Northern Ireland, UK.
3
Ontario Institute for Cancer Research, Toronto, Canada.
4
Department of Anatomic Pathology, University of Toronto, Canada.
5
Department of Medical Biophysics, University of Toronto, Canada; Ontario Institute for Cancer Research, Toronto, Canada.
6
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Northern Ireland, UK; Nuffield Department of Surgical Sciences, University of Oxford, UK.
7
Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Canada; Department of Radiation Oncology, University of Toronto, Canada. Electronic address: stanley.liu@sunnybrook.ca.

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.

KEYWORDS:

Primary prostate cancer; RXRA; Radiation resistance; microRNA; microRNA-191

PMID:
31874245
DOI:
10.1016/j.canlet.2019.12.025
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