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首页> 美国卫生研究院文献>BioResearch Open Access >miR-125b Regulation of Androgen Receptor Signaling Via Modulation of the Receptor Complex Co-Repressor NCOR2
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miR-125b Regulation of Androgen Receptor Signaling Via Modulation of the Receptor Complex Co-Repressor NCOR2

机译：通过调节受体复合物共阻遏物NCOR2对miR-125b雄激素受体信号的调节

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Recognition of micro-RNA function and their contribution to the biology of disease has given a new insight into disease mechanisms, with these discoveries potentially improving clinical diagnostic and therapeutic options. miR-125b has been identified as an important regulator in various cancers, including prostate cancer, but the mechanism of this regulation remains incompletely understood. In these studies, the effect of castration on miR-125b serum expression was evaluated in mice, simulating androgen deprivation. Furthermore, miR-125b expression was measured by quantitative real-time polymerase chain reaction (qRT-PCR) in LNCaP prostate cancer cells treated with the antiandrogen bicalutamide. Using LNCaP cells, the effect of miR-125b modulation on apoptotic protein and NCOR2, a co-repressor of androgen receptor (AR), was examined by Western blot. A 3′-untranslated region (UTR) luciferase-binding assay was performed to confirm that miR-125b targets NCOR2. We found that surgical castration induced an initial increase in the expression of circulating miR-125b in mice, while sham surgery did not. In addition, AR blockade via bicalutamide was associated with the rapid release of miR-125b into the cell culture medium of prostate cancer cells. A previously studied target of miR-125b, a regulator in the apoptotic pathway, BAK1, could not completely account for the role of miR-125b in prostate cancer. Thus, we looked for additional targets of miR-125b and found that NCOR2, which is a repressor of AR, is a direct target of miR-125b. We found that NCOR2 protein expression was blocked by mimics of miR-125b, and a luciferase-binding assay confirmed that NCOR2 is a direct target of miR-125b. Our data provide novel evidence that miR-125b is an important regulator of the AR with specific ramification for the effectiveness of antiandrogens and other hormonal therapies in prostate cancer.
机译：微小RNA功能及其对疾病生物学的贡献的认识为疾病机制提供了新的认识，这些发现潜在地改善了临床诊断和治疗选择。 miR-125b已被确定为包括前列腺癌在内的各种癌症的重要调节剂，但对该调节的机理仍未完全了解。在这些研究中，模拟雄激素剥夺，在小鼠中评估了去势对miR-125b血清表达的影响。此外，通过定量实时聚合酶链反应（qRT-PCR）在用抗雄激素比卡鲁胺治疗的LNCaP前列腺癌细胞中测量了miR-125b的表达。使用LNCaP细胞，通过蛋白质印迹检查了miR-125b调制对凋亡蛋白和NCOR2（一种雄激素受体（AR）的共阻遏物）的影响。进行3'-非翻译区（UTR）荧光素酶结合测定，以确认miR-125b靶向NCOR2。我们发现手术去势诱导了小鼠循环miR-​​125b表达的最初增加，而假手术却没有。另外，经由比卡鲁胺的AR阻断与miR-125b快速释放到前列腺癌细胞的细胞培养基中有关。先前研究的miR-125b靶标是细胞凋亡途径的调节剂BAK1，无法完全解释miR-125b在前列腺癌中的作用。因此，我们寻找了miR-125b的其他靶标，发现作为AR阻遏物的NCOR2是miR-125b的直接靶标。我们发现，miR-125b的模拟物阻止了NCOR2的蛋白表达，荧光素酶结合试验证实NCOR2是miR-125b的直接靶标。我们的数据提供了新的证据，证明miR-125b是AR的重要调节剂，对抗雄激素和其他激素疗法在前列腺癌中的有效性具有特定的影响。

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