miR-145 suppress the androgen receptor in prostate cancer cells and correlates to prostate cancer prognosis
miR-145 suppress the androgen receptor in prostate cancer cells and correlates to prostate cancer prognosis
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DOI：
10.1093/carcin/bgv063
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发表时间：
2015-08-01
期刊：
影响因子：
4.7
通讯作者：
Ceder, Yvonne
中科院分区：
文献类型：
--
作者：
Larne, Olivia;Hagman, Zandra;Ceder, Yvonne
通过雄激素受体（AR）的雄激素信号传导对于前列腺癌的发生、发展和转化为致命的去势抵抗状态至关重要。本研究的目的是表征miR-145解除调控促进前列腺癌进展的机制。通过定量逆转录聚合酶链反应测量的miR-145水平，在一个特征明确的前列腺癌队列中，被发现与转移的发生、生存和雄激素剥夺治疗反应呈负相关。在前列腺癌细胞中引入异位miR-145，在转录物和蛋白质水平上对AR产生抑制作用，以及其活性和下游靶点前列腺特异性抗原（PSA）、钾化钾素相关肽酶2和TMPRSS2。这种调节被证明是通过ago2特异性免疫沉淀直接结合介导的，但也有迹象表明协同AR激活。这些发现在临床前列腺标本中得到证实，miR-145与AR表达以及血清PSA水平呈负相关。此外，miR-145被发现在体外调节雄激素依赖性细胞的生长。我们的研究结果为治疗干预提出了新的可能性，因为miR-145可能会减少肿瘤中干细胞和AR的表达量，从而减少向致命的去势抵抗型前列腺癌的转化。
Androgen signalling through the androgen receptor (AR) is essential for prostate cancer initiation, progression and transformation to the lethal castration-resistant state. The aim of this study was to characterize the mechanisms by which miR-145 deregulation contribute to prostate cancer progression. The miR-145 levels, measured by quantitative reverse transcription-polymerase chain reaction, were found to inversely correlate with occurrence of metastases, survival and androgen deprivation therapy response in a well-characterized prostate cancer cohort. Introduction of ectopic miR-145 in prostate cancer cells generated an inhibitory effect on the AR at both transcript and protein levels as well as its activity and downstream targets prostate-specific antigen (PSA), kallikrein-related peptidase 2 and TMPRSS2. The regulation was shown to be mediated by direct binding using Ago2-specific immunoprecipitation, but there was also indication of synergetic AR activation. These findings were verified in clinical prostate specimens by demonstrating inverse correlations between miR-145 and AR expression as well as serum PSA levels. In addition, miR-145 was found to regulate androgen-dependent cell growth in vitro. Our findings put forward novel possibilities of therapeutic intervention, as miR-145 potentially could decrease both the stem cells and the AR expressing bulk of the tumour and hence reduce the transformation to the deadly castration-resistant form of prostate cancer.