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

Cancer Lett. 2020 Mar 31;473:107-117. doi: 10.1016/j.canlet.2019.12.025. Epub 2019 Dec 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alitretinoin / administration & dosage
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Biomarkers, Tumor / metabolism*
  • Cell Line, Tumor
  • Chemoradiotherapy, Adjuvant / methods
  • Disease-Free Survival
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Knockdown Techniques
  • Humans
  • Kallikreins / blood
  • Kaplan-Meier Estimate
  • Male
  • Mice
  • MicroRNAs / agonists
  • MicroRNAs / metabolism*
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Recurrence, Local / blood
  • Neoplasm Recurrence, Local / genetics*
  • Neoplasm Recurrence, Local / pathology
  • Neoplasm Recurrence, Local / prevention & control
  • Primary Cell Culture
  • Prognosis
  • Prostate / pathology
  • Prostate / surgery
  • Prostate-Specific Antigen / blood
  • Prostatectomy
  • Prostatic Neoplasms / blood
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / therapy*
  • Radiation Tolerance / drug effects
  • Radiation Tolerance / genetics*
  • Retinoid X Receptor alpha / agonists
  • Retinoid X Receptor alpha / genetics*
  • Survival Rate
  • Time Factors
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • MIRN191 microRNA, human
  • MicroRNAs
  • RXRA protein, human
  • Retinoid X Receptor alpha
  • Alitretinoin
  • Kallikreins
  • kallikrein-related peptidase 3, human
  • Prostate-Specific Antigen

Grant support