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.

中文翻译：

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miR-191 通过与 RXRA 的相互作用促进前列腺癌的辐射抗性。

放射治疗是前列腺癌的常见治疗方法，但复发仍然是一个问题。MicroRNA 表达在前列腺癌中发生改变，可能会促进治疗抵抗。通过对 TCGA 和 CPC-GENE 患者队列的生物信息学分析，我们发现肿瘤与正常组织相比，miR-191 表达更高，并且在较高的 Gleason 评分中表达增加。体外和体内实验表明 miR-191 过表达促进辐射存活，并有助于更具侵略性的表型。类视黄醇 X 受体 α，RXRA，被发现是 miR-191 的新靶点，并且敲低重现了放射抗性。此外，用 RXRA 激动剂 9-顺式-视黄酸治疗前列腺癌细胞恢复了放射敏感性。支持这种关系，具有高 miR-191 和低 RXRA 丰度的患者经历了更快的生化复发。减少的 RXRA 转化为放疗后远处失败的更高风险。值得注意的是，这种 miR-191/RXRA 相互作用在源自放射复发性前列腺癌的新型原代细胞系中是保守的。总之，我们的研究结果表明 miR-191 可促进放疗后前列腺癌的存活，并强调类视色素是改善放疗反应的潜在选择。