Tumor suppressor microRNAs, miR-100 and -125b, are regulated by 1,25-dihydroxyvitamin D in primary prostate cells and in patient tissue.
Tumor suppressor microRNAs, miR-100 and -125b, are regulated by 1,25-dihydroxyvitamin D in primary prostate cells and in patient tissue.
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DOI：
10.1158/1940-6207.capr-12-0253
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发表时间：
2013-05
期刊：
影响因子：
--
通讯作者：
Nonn L
中科院分区：
文献类型：
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作者：
Giangreco AA;Vaishnav A;Wagner D;Finelli A;Fleshner N;Van der Kwast T;Vieth R;Nonn L
MiR-100和miR-125b在许多癌症中缺失，具有肿瘤抑制的潜在功能。研究人员利用45名维生素D3随机试验患者的原发性前列腺上皮培养和激光捕获显微解剖前列腺上皮，确定miR-100和-125b是1,25-二羟基维生素D3 （1,25 d）的靶点。在患者中，肿瘤组织中的miR-100和-125b水平明显低于良性前列腺组织。同样，miR-100和-125b在原代前列腺癌细胞中的表达低于来自良性前列腺的细胞。前列腺癌和良性上皮中1,25 d的前列腺浓度与这些miRNA水平呈正相关，表明前列腺癌患者可能仍然受益于维生素D3。在细胞实验中，125d对这些mirna的上调依赖于维生素D受体。在存在或不存在1,25 d的情况下转染pre-miR-100和pre-miR-125b可降低癌细胞RWPE-2的侵袭性。Pre-miR-100和pre-miR-125b分别降低原代细胞和癌细胞的增殖。转染Pre-miR-125b可抑制PCa细胞的迁移和克隆生长，而在正常细胞中敲低miR-125b可增加迁移，表明其具有肿瘤抑制功能。1,25 d以mirna依赖的方式抑制了这些mirna， E2F3和Plk1先前真正的mRNA靶点的表达。综上所述，这些研究结果表明，补充维生素D3增加了患者前列腺组织中的肿瘤抑制mirna，提供了证据，表明mirna可能是维生素D3活性在预防和早期治疗前列腺癌中的关键生理介质。
MiR-100 and miR-125b are lost in many cancers and have potential function as tumor suppressors. Using both primary prostatic epithelial cultures and laser-capture-microdissected prostate epithelium from 45 patients enrolled in a vitamin D3 randomized trial, we identified miR-100 and -125b as targets of 1,25-dihydroxyvitamin D3 (1,25D). In patients, miR-100 and -125b levels were significantly lower in tumor tissue than in benign prostate. Similarly, miR-100 and -125b were lower in primary PCa cells than in cells derived from benign prostate. Prostatic concentrations of 1,25D positively correlated with these miRNA levels in both PCa and benign epithelium, demonstrating that PCa patients may still benefit from vitamin D3. In cell assays, upregulation of these miRNAs by 1,25D was vitamin D receptor-dependent. Transfection of pre-miR-100 and pre-miR-125b in the presence or absence of 1,25D decreased invasiveness of cancer cell, RWPE-2. Pre-miR-100 and pre-miR-125b decreased proliferation in primary cells and cancer cells respectively. Pre-miR-125b transfection suppressed migration and clonal growth of PCa cells while knockdown of miR-125b in normal cells increased migration indicates a tumor suppressor function. 1,25D suppressed expression of previously bona fide mRNA targets of these miRNAs, E2F3 and Plk1, in a miRNA-dependent manner. Together, these findings demonstrate that vitamin D3 supplementation augments tumor suppressive miRNAs in patient prostate tissue, providing evidence that miRNAs could be key physiologic mediators of vitamin D3 activity in prevention and early treatment of PCa.