Androgen Signalling Laboratory, Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
Hum Mol Genet. 2012 Jul 15;21(14):3112-27. doi: 10.1093/hmg/dds139. Epub 2012 Apr 14.
MicroRNAs (miRs) play an important role in the development of many complex human diseases and may have tumour suppressor or oncogenic (oncomir) properties. Prostate cancer is initially an androgen-driven disease, and androgen receptor (AR) remains a key driver of growth even in castration-resistant tumours. However, AR-mediated oncomiR pathways remain to be elucidated. We demonstrate that miR-27a is an androgen-regulated oncomir in prostate cancer, acting via targeting the tumour suppressor and AR corepressor, Prohibitin (PHB). Increasing miR-27a expression results in reduced PHB mRNA and protein levels, and increased expression of AR target genes and prostate cancer cell growth. This involves a novel mechanism for androgen-mediated miR regulation, whereby AR induces a transient increase in miR-23a27a24-2 transcription, but more significantly accelerates processing of the primiR-23a27a24-2 cluster. Androgens therefore regulate miR-27a expression both transcriptionally (via AR binding to the cluster promoter) and post-transcriptionally (accelerating primiR processing to the mature form). We further show that a miR-27a anti-sense oligonucleotide, by opposing the effects of mir-27a, has therapeutic potential in prostate cancer.
微小 RNA（miRs）在许多复杂人类疾病的发展中起着重要作用，并且可能具有肿瘤抑制或致癌（oncomir）特性。前列腺癌最初是一种雄激素驱动的疾病，即使在去势抵抗性肿瘤中，雄激素受体（AR）仍然是生长的关键驱动因素。然而，AR 介导的 oncomiR 途径仍有待阐明。我们证明 miR-27a 是前列腺癌中的一种雄激素调节的致癌 miRNA，通过靶向肿瘤抑制因子和 AR 核心抑制因子 Prohibitin（PHB）发挥作用。增加 miR-27a 的表达会导致 PHB mRNA 和蛋白水平降低，以及 AR 靶基因和前列腺癌细胞生长的增加。这涉及到一种新的雄激素介导的 miR 调节机制，其中 AR 诱导 miR-23a27a24-2 转录的短暂增加，但更显著地加速了 primiR-23a27a24-2 簇的加工。因此，雄激素既可以通过 AR 结合到簇启动子上进行转录调控（transcriptionally）（通过 AR 结合到簇启动子上），也可以通过加速 primiR 向成熟形式的加工进行转录后调控（post-transcriptionally）。我们进一步表明，miR-27a 的反义寡核苷酸通过拮抗 mir-27a 的作用，在前列腺癌中有治疗潜力。
