Department of OB/GYN, University of Florida, Box 100294, Gainesville, FL 32610, USA.
Mol Hum Reprod. 2010 Mar;16(3):215-27. doi: 10.1093/molehr/gap093. Epub 2009 Nov 11.
Aberrant expression of microRNAs (miRNAs), including miR-21, and alteration of their target genes stability have been associated with cellular transformation and tumorigenesis. We investigated the expression, regulation and function of miR-21 in leiomyomas which develop from myometrial cellular transformation. The results indicated that miR-21 is over-expressed in leiomyomas with specific elevation during the secretory phase of the menstrual cycle and in women who received Depo-Provera and oral contraceptives, but reduced due to GnRHa therapy (P < 0.05). Bioinformatic analysis of microarray gene expression profiles previously obtained from the above cohorts, and myometrial smooth muscle cells (MSMC) and leiomyoma smooth muscle cells (LSMC) treated with GnRHa, transforming growth factor (TGF)-beta and TGF-beta receptor type II (TGF-betaRII) antisense oligomer, indicated that a number of miR-21-predicted target genes were co-expressed and differentially regulated in these cohorts. Gain- and loss-of-function of miR-21 in MSMC, LSMC, transformed LSMC and leiomyosarcoma cell line (SKLM-S1) resulted in differential expression of many genes, including some of the miR-21-predicted/validated target genes, PTEN, PDCD4 and E2F1, and TGF-betaRII, in a cell-specific manner. Gain-of miR-21 function in MSMC and LSMC reduced TGF-beta-induced expression of fibromodulin and TGF-beta-induced factor (P < 0.05), and moderately altered the rate of cell growth and caspase-3/7 activity in these cells. We concluded that miR-21 is aberrantly expressed and hormonally regulated in leiomyomas where, through functional interaction with ovarian steroids and the TGF-beta signaling pathway, either directly or indirectly regulates a number of genes whose products are critical in leiomyoma growth and regression as well as their potential cellular transformation.
微小 RNA（miRNA）的异常表达，包括 miR-21，以及它们的靶基因稳定性的改变，与细胞转化和肿瘤发生有关。我们研究了 miR-21 在由子宫平滑肌细胞转化而来的子宫肌瘤中的表达、调控和功能。结果表明，miR-21 在子宫肌瘤中过度表达，在月经周期的分泌期特异性升高，在接受 Depo-Provera 和口服避孕药的女性中升高，而在 GnRHa 治疗后降低（P<0.05）。对上述队列中获得的微阵列基因表达谱的生物信息学分析，以及用 GnRHa、转化生长因子（TGF）-β和 TGF-β 受体 II（TGF-βRII）反义寡核苷酸处理的子宫平滑肌细胞（MSMC）和子宫肌瘤平滑肌细胞（LSMC），表明许多 miR-21 预测的靶基因在这些队列中共同表达并受到差异调控。在 MSMC、LSMC、转化的 LSMC 和 leiomyosarcoma 细胞系（SKLM-S1）中，miR-21 的增益和丢失功能导致许多基因的差异表达，包括一些 miR-21 预测/验证的靶基因，如 PTEN、PDCD4 和 E2F1，以及 TGF-βRII，以细胞特异性的方式。在 MSMC 和 LSMC 中，miR-21 功能的获得降低了 TGF-β 诱导的纤维调蛋白和 TGF-β 诱导因子的表达（P<0.05），并适度改变了这些细胞的细胞生长速度和 caspase-3/7 活性。我们得出结论，miR-21 在子宫肌瘤中异常表达并受激素调节，通过与卵巢类固醇和 TGF-β 信号通路的功能相互作用，直接或间接地调节了许多基因的表达，这些基因的产物在子宫肌瘤的生长和消退以及它们潜在的细胞转化中至关重要。
