Radioresistance remains to be a major obstacle in the management of patients with advanced prostate cancer (PCa). We have identified a mature miR-17-3p processed from the 3′ arm of precursor miR-17, which appeared to be able to inhibit three major antioxidant enzymes located in mitochondria, i.e., manganese superoxide dismutase (MnSOD), glutathione peroxidase 2 (Gpx2), and thioredoxin reductase 2 (TrxR2). Here we show that upregulation of miR-17-3p remarkably sensitized PCa cells to ionizing radiation (IR). Reductions of the three antioxidants led to increasing cellular reactive oxygen species (ROS) accumulation as well as declining mitochondrial respiration. The miR-17-3p-mediated dysfunction of mitochondrial antioxidants apparently sensitizing IR therapy was manifested in vitro and in vivo. Substantially, the miR-17-3p effect on suppression of the antioxidants can be efficiently eliminated or attenuated by transfecting with either an miR-17-3p inhibitor or each of the related antioxidant cDNA expression constructs. Overall, in addition to the insights into the functional assessments for the duplex of miR-17-5p and miR-17-3p, the present study highlights the rigorous evidence that demonstrated suppression of multiple mitochondrial antioxidants by a single microRNA (miRNA), thereby providing a promising approach to improve radiotherapy for advanced PCa by targeting mitochondrial function.

放射抗性仍然是晚期前列腺癌（PCa）患者治疗的主要障碍。我们已经鉴定出由前体 miR-17 的 3' 臂加工而成的成熟 miR-17-3p，它似乎能够抑制线粒体中的三种主要抗氧化酶，即锰超氧化物歧化酶 (MnSOD)、谷胱甘肽过氧化物酶 2 ( Gpx2) 和硫氧还蛋白还原酶 2 (TrxR2)。在这里，我们发现 miR-17-3p 的上调显着使 PCa 细胞对电离辐射 (IR) 敏感。三种抗氧化剂的减少导致细胞活性氧（ROS）积累增加以及线粒体呼吸减弱。miR-17-3p 介导的线粒体抗氧化剂功能障碍明显使 IR 治疗敏感，这在体外和体内都有体现。基本上，通过用 miR-17-3p 抑制剂或每种相关抗氧化剂 cDNA 表达构建体转染，可以有效消除或减弱 miR-17-3p 对抗氧化剂抑制的作用。总体而言，除了深入了解 miR-17-5p 和 miR-17-3p 双链体的功能评估外，本研究还强调了证明单个 microRNA (miRNA) 抑制多种线粒体抗氧化剂的严格证据，从而通过靶向线粒体功能，提供了一种有前途的方法来改善晚期 PCa 的放射治疗。