microRNAs and DICER1 are regulated by 1,25-dihydroxyvitamin D in prostate stroma.
microRNAs and DICER1 are regulated by 1,25-dihydroxyvitamin D in prostate stroma.
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DOI：
10.1016/j.jsbmb.2017.01.004
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发表时间：
2017-03
期刊：
影响因子：
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通讯作者：
Nonn L
中科院分区：
文献类型：
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作者：
Dambal S;Giangreco AA;Acosta AM;Fairchild A;Richards Z;Deaton R;Wagner D;Vieth R;Gann PH;Kajdacsy-Balla A;Van der Kwast T;Nonn L
维生素D缺乏会增加致命性前列腺癌（PCa）的风险，大多数老年男性都缺乏维生素D。尽管前列腺癌起源于上皮，但周围的间质对上皮具有激素调节控制，并有助于癌变。在此，我们描述了人类前列腺基质中活性激素二羟维生素D（1，25（OH）2D）对microRNA（miR）的调节。1，25（OH）2D结合维生素D受体（VDR）转录因子以调节基因表达，包括miR，其已成为蛋白质表达的有效调节剂。通过在原代人前列腺基质细胞（PrS）中进行谱分析来鉴定1，25（OH）2D调节的miR，并且随后在来自维生素D3临床试验（N=45）的激光捕获显微切割的前列腺基质组织中验证了三种miR，miR-126- 3 p、miR 154- 5 p和miR-21- 5 p。1，25（OH）2D对这些miR的调节具有VDR依赖性。这些miR的已知和推定mRNA靶点的网络分析富含癌症和炎症途径，与基质和维生素D在致癌作用中的已知作用一致。miR加工核糖核酸酶DICER 1的表达与临床试验样本中的维生素D代谢物水平呈正相关。在170例匹配的PCa患者的组织微阵列中，DICER 1的高上皮/间质比率与生化复发显著相关（OR 3.1，p=0.03）。总之，这些结果强调了前列腺基质在调节对激素1，25（OH）2D的反应中的作用，并鉴定了miR和DICER 1在人前列腺基质中受到调节。1，25（OH）2D对间质DICER 1的调节也可能在预防侵袭性PCa方面具有临床相关性。
Vitamin D deficiency increases the risk of lethal prostate adenocarcinomas (PCa) and the majority of older men are deficient. Although PCa arises from the epithelium, the surrounding stroma has hormonal regulatory control over the epithelium and contributes to carcinogenesis. Herein, we describe regulation of microRNAs (miRs) by the active hormone dihydroxyvitamin D (1,25(OH)2D) in human prostate stroma. 1,25(OH)2D binds the vitamin D receptor (VDR) transcription factor to regulate gene expression, including miRs, which have emerged as potent regulators of protein expression. 1,25(OH)2D -regulated miRs were identified by profiling in primary human prostatic stromal cells (PrS) and three miRs, miR-126-3p, miR 154-5p and miR-21-5p were subsequently validated in laser-capture micro-dissected prostate stromal tissue from a vitamin D3 clinical trial (N=45). Regulation of these miRs by 1,25(OH)2D was VDR-dependent. Network analysis of known and putative mRNA targets of these miRs was enriched with cancer and inflammation pathways, consistent with known roles of stroma and of vitamin D in carcinogenesis. Expression of the miR processing ribonuclease, DICER1, positively correlated with vitamin D metabolite levels in the clinical trial specimens. High epithelial/stromal ratios of DICER1 were significantly associated biochemical recurrence (OR 3.1, p=0.03) in a tissue microarray of 170 matched PCa patients. In summary, these results underscore the role of the prostate stroma in regulating responses to the hormone 1,25(OH)2D and identified miRs and DICER1 as being regulated in human prostate stroma. Regulation of stromal DICER1 by 1,25(OH)2D may also have clinical relevance in protection against aggressive PCa.