miR-200c is aberrantly expressed in leiomyomas in an ethnic-dependent manner and targets ZEBs, VEGFA, TIMP2, and FBLN5.
miR-200c is aberrantly expressed in leiomyomas in an ethnic-dependent manner and targets ZEBs, VEGFA, TIMP2, and FBLN5.
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DOI：
10.1530/erc-12-0007
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发表时间：
2012-08
影响因子：
3.9
通讯作者：
Chegini N
中科院分区：
文献类型：
--
作者：
Chuang TD;Panda H;Luo X;Chegini N
MicroRNA-200c (miR-200c) 通过抑制特定靶基因与细胞转变、肿瘤发生和组织纤维化相关。我们探讨了 miR-200c 在平滑肌瘤 (LYO)（具有纤维化特征的良性子宫肿瘤）发生中的表达和功能。使用来自未经治疗和接受激素治疗（GNRH 激动剂 (GNRHa)、Depo-Provera 和口服避孕药）的患者的 LYO 和相匹配的子宫肌层 (MYO；n=76)，我们发现与 MYO 相比，LYO 中 miR-200c 的表达水平显着降低 (P<0.05)。与白种人、经历异常子宫出血的患者和接受 GNRHa 治疗的患者相比，非裔美国人的 LYO 水平较低。 miR-200c 在分离的平滑肌瘤细胞 (LSMC)、子宫肌层平滑肌细胞 (MSMC) 和平滑肌肉瘤细胞系 (SKLM-S1) 中的功能获得抑制了 ZEB1/ZEB2 mRNA 和蛋白，同时 E-钙粘蛋白 (CDH1) 增加，波形蛋白表达减少，表型改变，并抑制 MSMC 和 LSMC 增殖。通过与微阵列分析确定的 TIMP2、FBLN5 和 VEGFA 各自的 3' UTR 以及其他基因的相互作用，我们进一步验证了 TIMP2、FBLN5 和 VEGFA 作为 miR-200c 的直接靶标。在组织水平上，LYO 表达的 TIMP2 和 FBLN5 mRNA 水平较低，但蛋白质表达增加，这在一定程度上由于激素暴露而改变。鉴于 ZEB、VEGFA、FBLN5 和 TIMP2 对促进细胞转变、血管生成和基质重塑的细胞活动的调节功能，我们得出结论，miR-200c 表达的改变可能对 LYO 生长的结果、其间质和纤维化特征的维持以及可能的相关症状产生显着影响。
MicroRNA-200c (miR-200c) through repression of specific target genes has been associated with cellular transition, tumorigenesis, and tissue fibrosis. We explored the expression and functional aspects of miR-200c in genesis of leiomyomas (LYO), benign uterine tumors with fibrotic characteristic. Using LYO and matched myometrium (MYO; n=76) from untreated and from patients exposed to hormonal therapies (GNRH agonist (GNRHa), Depo-Provera, and oral contraceptives), we found that miR-200c was expressed at significantly lower levels (P<0.05) in LYO as compared with MYO. These levels were lower in LYO from African Americans as compared with Caucasians, patients experiencing abnormal uterine bleeding and those exposed to GNRHa therapy. Gain-of-function of miR-200c in isolated leiomyoma smooth muscle cells (LSMCs), myometrial smooth muscle cells (MSMCs), and leiomyosarcoma cell line (SKLM-S1) repressed ZEB1/ZEB2 mRNAs and proteins, with concurrent increase in E-cadherin (CDH1) and reduction in vimentin expression, phenotypic alteration, and inhibition of MSMC and LSMC proliferations. We further validated TIMP2, FBLN5, and VEGFA as direct targets of miR-200c through interaction with their respective 3′ UTRs, and other genes as determined by microarray analysis. At tissue levels, LYO expressed lower levels of TIMP2 and FBLN5 mRNAs but increased protein expressions, which to some extent altered due to hormonal exposure. Given the regulatory functions of ZEBs, VEGFA, FBLN5, and TIMP2 on cellular activities that promote cellular transition, angiogenesis, and matrix remodeling, we concluded that altered expression of miR-200c may have a significant impact on the outcome of LYO growth, maintenance of their mesenchymal and fibrotic characteristics, and possibly their associated symptoms.