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针对病种:前列腺癌
发表时间:2016年
发表国家:美国
登载刊物:前列腺癌
研究单位:生物医学科学研究所,阿尔斯特大学科尔雷恩,英国;学校的医学、 牙科和生物医学科学,贝尔法斯特女王大学,贝尔法斯特,英国;部的细胞病理学、 西方健康和社会关怀信任,Altnagelvin 地区医院,德里英国
研究人员:色哈娜 M 兰澈,卡奥拉 M 奥尼尔,米彻尔 M 麦肯纳,等
主要结论:我们的研究结果提供证据表明miR-200c和miR-141在PCa细胞中的表观遗传调节。 我们建议剖析其表达和甲基化状态可能有潜力作为新型生物标志物或焦点的治疗干预在PCa的诊断和预后.
Prostate, 2016, 76(13):1146-1159.
Regulation of miR-200c and miR-141 by Methylation in Prostate Cancer
Seodhna M. Lynch, Karla M. O'Neill, Michael M. Mckenna, et al
Biomedical Sciences Research Institute, University of Ulster, Coleraine, UK; School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK; Department of Cellular Pathology, Western Health and Social Care Trust, Altnagelvin Area Hospital, Derry, UK
BACKGROUND:
In prostate cancer (PCa), abnormal expression of several microRNAs (miRNAs) has been previously reported. Increasing evidence shows that aberrant epigenetic regulation of miRNAs is a contributing factor to their altered expression in cancer. In this study, we investigate whether expression of miR-200c and miR-141 in PCa is related to the DNA methylation status of their promoter.
METHODS:
PCR analysis of miR-200c and miR-141, and CpG methylation analysis of their common promoter, was performed in PCa cell-lines and in archived prostate biopsy specimens. The biological significance of miR-200c and miR-141 expression in prostate cancer cells was assessed by a series of in vitro bioassays and the effect on proposed targets DNMT3A and TET1/TET3 was investigated. The effect on promoter methylation status in cells treated with demethylating agents was also examined.
RESULTS:
miR-200c and miR-141 are both highly elevated in LNCaP, 22RV1, and DU145 cells, but significantly reduced in PC3 cells. This correlates inversely with the methylation status of the miR-200c/miR-141 promoter, which is unmethylated in LNCaP, 22RV1, and DU145 cells, but hypermethylated in PC3. In PC3 cells, miR-200c and miR-141 expression is subsequently elevated by treatment with the demethylating drug decitabine (5-aza-2'deoxycytidine) and by knockdown of DNA methyltransferase 1 (DNMT1), suggesting their expression is regulated by methylation. Expression of miR-200c and miR-141 in prostate biopsy tissue was inversely correlated with methylation in promoter CpG sites closest to the miR-200c/miR-141 loci. In vitro, over-expression of miR-200c in PC3 cells inhibited growth and clonogenic potential, as well as inducing apoptosis. Expression of the genes DNMT3A and TET1/TET3 were down-regulated by miR-200c and miR-141 respectively. Finally, treatment with the soy isoflavone genistein caused demethylation of the promoter CpG sites closest to the miR-200c/miR-141 loci resulting in increased miR-200c expression.
CONCLUSIONS:
Our findings provide evidence that miR-200c and miR-141 are under epigenetic regulation in PCa cells. We propose that profiling their expression and methylation status may have potential as a novel biomarker or focus of therapeutic intervention in the diagnosis and prognosis of PCa.
美国《前列腺癌》2016, 76(13):1146-1159.
前列腺癌中miR-200c和miR-141的甲基化调控
生物医学科学研究所,阿尔斯特大学科尔雷恩,英国;学校的医学、 牙科和生物医学科学,贝尔法斯特女王大学,贝尔法斯特,英国;部的细胞病理学、 西方健康和社会关怀信任,Altnagelvin 地区医院,德里英国
背景︰
在前列腺癌 (PCa),先前报道的异常表达的几种小分子Rna (Mirna)。越来越多的证据表明,异常的表观遗传调控的Mirna是向他们表达改变在癌症的一个因素。在此研究中,我们调查是否miR-200 c 和 miR-141 在 PCa 的表达与启动子的 DNA 甲基化状态有关。
方法:
在PCa细胞系和存档的前列腺活检标本中进行miR-200c和miR-141的PCR分析以及它们的共同启动子的CpG甲基化分析。 通过一系列体外生物测定评估miR-200c和miR-141在前列腺癌细胞中的表达的生物学意义,并研究了对提出的靶标DNMT3A和TET1 / TET3的影响。 还检查了用去甲基化剂处理的细胞中对启动子甲基化状态的影响。
结果:
miR-200c和miR-141在LNCaP,22RV1和DU145细胞中都高度升高,但在PC3细胞中显着降低。这与miR-200c / miR-141启动子的甲基化状态相反,miR-200c / miR-141启动子在LNCaP,22RV1和DU145细胞中未甲基化,但在PC3中高甲基化。在PC3细胞中,miR-200c和miR-141的表达随后通过用去甲基化药物地西他滨(5-氮杂-2'-脱氧胞苷)处理和通过敲除DNA甲基转移酶1(DNMT1)而升高,表明它们的表达受甲基化调节。 miR-200c和miR-141在前列腺活检组织中的表达与最接近miR-200c / miR-141基因座的启动子CpG位点的甲基化反相关。在体外,miR-200c在PC3细胞中的过表达抑制生长和克隆形成潜能,以及诱导凋亡。基因DNMT3A和TET1 / TET3的表达分别被miR-200c和miR-141下调。最后,用大豆异黄酮染料木黄酮的处理导致最接近miR-200c / miR-141基因座的启动子CpG位点的去甲基化,导致miR-200c表达增加。
结论:
我们的研究结果提供证据表明miR-200c和miR-141在PCa细胞中的表观遗传调节。 我们建议剖析其表达和甲基化状态可能有潜力作为新型生物标志物或焦点的治疗干预在PCa的诊断和预后。
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