Endometrial miR-200c is Altered During Transformation into Cancerous States and Targets the Expression of ZEBs, VEGFA, FLT1, IKKβ, KLF9, and FBLN5
Endometrial miR-200c is Altered During Transformation into Cancerous States and Targets the Expression of ZEBs, VEGFA, FLT1, IKKβ, KLF9, and FBLN5
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DOI：
10.1177/1933719112438448
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发表时间：
2012-08-01
影响因子：
2.9
通讯作者：
Chegini, Nasser
中科院分区：
文献类型：
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作者：
Panda, Harekrushna;Pelakh, Leslie;Chegini, Nasser
包括miR-200家族在内的许多microrna （mirna）在子宫内膜异位症和子宫内膜癌中异常表达。在这里，我们评估了miR-200c在正常子宫内膜活检（N = 15）、接受激素治疗的子宫内膜组织（N = 20）和I-III级子宫内膜癌（N = 17）中的表达和功能方面。与绝经前后的子宫内膜组织相比，在黄体中期和晚期的正常子宫内膜活检中，以及在子宫内膜肿瘤中，miR-200c的表达水平升高（P < 0.05），其时间表达模式与zeb的表达呈负相关。E-cadherin （CDH1）的表达变化多样，但表达水平较低，特别是在子宫内膜组织和子宫内膜肿瘤中。与增殖期相比，暴露于Depo-Provera和促性腺激素释放激素激动剂GnRHa的患者子宫内膜中zeb和CDH1的表达有降低的趋势；然而，用17 β -雌二醇、孕酮和醋酸甲孕酮处理石川细胞对miR-200c和zeb的表达影响不大，不影响CDH1的表达。在Ishikawa细胞中，miR-200c功能的获得通过与各自的3'非翻译区直接相互作用，在转录和翻译水平上抑制zeb以及VEGFA、FLT1、IKK β和KLF9的表达，并提高其增殖速度。这些结果表明，子宫内膜miR-200c的表达在正常向癌变的过程中发生了动态变化；可能受到激素环境的影响，并通过靶向在细胞转化、炎症和血管生成中具有关键调节功能的特定基因的表达，可能影响正常和疾病进展期间的这些事件。
A number of microRNAs (miRNAs), including miR-200 family, are aberrantly expressed in endometriosis and endometrial cancer. Here we assessed the expression and functional aspects of miR-200c in endometrial tissues (N = 52) from normal endometrial biopsies (N = 15), endometrial tissues including those exposed to hormonal therapies (N = 20), and grade I-III endometrial cancer (N = 17). miR-200c expression was elevated in normal endometrial biopsies from mid- and late-luteal phase, and in endometrial tumors as compared to endometrial tissues from peri- and postmenopausal period (P < .05) and its pattern of temporal expression displayed an inverse relationship with the expression of ZEBs. The expression of E-cadherin (CDH1) varied, but expressed at low levels, specifically in endometrial tissues and endometrial tumors. The endometrial expression of ZEBs and CDH1 in patients who were exposed to Depo-Provera and gonadotropin-releasing hormone agonist GnRHa displayed a trend toward lower expression as compared to proliferative phase; however, treatment of Ishikawa cells with 17 beta-estradiol, progesterone, and medroxy progesterone acetate had modest effects on the expression of miR-200c and ZEBs without affecting CDH1 expression. Gain of function of miR-200c in Ishikawa cells repressed ZEBs, as well as VEGFA, FLT1, IKK beta, and KLF9 expression at transcriptional and translational levels through direct interaction with their respective 3'untranslated regions and increased the rate of their proliferation. These results indicated that endometrial miR-200c expression undergoes dynamic changes during transition from normal into cancerous states; possibly influenced by hormonal milieu and by targeting the expression of specific genes with key regulatory functions in cellular transformation, inflammation, and angiogenesis may influence these events during normal and disease progression.