Mechanisms underlying aberrant expression of miR-29c in uterine leiomyoma
Mechanisms underlying aberrant expression of miR-29c in uterine leiomyoma
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DOI：
10.1016/j.fertnstert.2015.09.020
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发表时间：
2016-01-01
影响因子：
6.7
通讯作者：
Khorram, Omid
中科院分区：
文献类型：
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作者：
Chuang, Tsai-Der;Khorram, Omid
目的：为了确定miR-29 c及其靶基因在平滑肌瘤中的表达以及NF-κ B、特异性蛋白1（SP1）和DNA甲基化在其调节中的作用。设计：实验研究。设置：学术研究实验室。患者：因平滑肌瘤接受子宫切除术的妇女。干预：miR-29 c的过表达和低表达;转录因子的阻断。主要结果测量：miR-29 c及其靶基因在子宫肌瘤中的表达水平以及转录因子阻断对miR-29 c表达的影响。结果：与子宫肌层相比，子宫肌瘤中miR-29 c的表达水平显著降低，且与其靶基因COL 3A 1和DNMT 3A的表达呈负相关。miR-29 c功能的获得在蛋白和mRNA水平上抑制COL 3A 1和DNMT 3A的表达，抑制COL 3A 1的分泌和细胞增殖速率。miR-29 c功能的丧失具有相反的效果。E-2、P及其组合抑制平滑肌瘤平滑肌细胞（LSMC）中的miR-29 c。磷酸化NF-κ B（p65）和SP 1蛋白在平滑肌瘤中表达显著增加。siRNA敲除SP1和DNMT 3A或其特异性抑制剂显著增加了miR-29 c的表达，同时抑制了siRNA处理的细胞中细胞和分泌的COL 3A 1。结论：miR-29 c在平滑肌瘤中的表达受到抑制，导致其靶基因COL 3A 1和DNMT 3A的表达增加。miR-29 c在LSMC中的抑制主要由SP1、NF-kB信号传导和表观遗传修饰介导。总的来说，这些结果表明miR-29 c在平滑肌瘤发病机制中的重要作用。(C)2016年，美国生殖医学会（American Society for Reproductive Medicine）
Objective: To determine the expression of miR-29c and its target genes in leiomyoma and the role of NF-kappa B, specific protein 1 (SP1), and DNA methylation in its regulation.Design: Experimental study.Setting: Academic research laboratory.Patient(s): Women undergoing hysterectomy for leiomyoma.Intervention(s): Over-and underexpression of miR-29c; blockade of transcription factors.Main Outcome Measure(s): MiR-29c and its target gene levels in leiomyoma and the effects of blockade of transcription factors on miR-29c expression.Result(s): Leiomyoma as compared with myometrium expressed significantly lower levels of miR-29c, with an inverse relationship with expression of its targets, COL3A1 and DNMT3A. Gain of function of miR-29c inhibited the expression of COL3A1 and DNMT3A at protein and mRNA levels, secreted COL3A1, and rate of cell proliferation. Loss of function of miR-29c had the opposite effect. E-2, P, and their combination inhibited miR-29c in leiomyoma smooth muscle cells (LSMC). Phosphorylated NF-kappa B (p65) and SP1 protein expression were significantly increased in leiomyoma. SiRNA knockdown of SP1 and DNMT3A or their specific inhibitors significantly increased the expression of miR-29c, accompanied by the inhibition of cellular and secreted COL3A1 in siRNA-treated cells. Knockdown of p65 also induced miR-29c expression but had no effect on COL3A1 expression.Conclusion(s): MiR-29c expression is suppressed in leiomyoma, resulting in an increase in expression of its targets COL3A1 and DNMT3A. The suppression of miR-29c in LSMC is primarily mediated by SP1, NF-kB signaling, and epigenetic modification. Collectively, these results indicate a significant role for miR-29c in leiomyoma pathogenesis. (C) 2016 by American Society for Reproductive Medicine.