子宫内膜 miR-181a 和 miR-98 的表达在从正常状态向癌变状态转变过程中发生改变，靶向 PGR、PGRMC1、CYP19A1、DDX3X 和 TIMP3。
Endometrial miR-181a and miR-98 expression is altered during transition from normal into cancerous state and target PGR, PGRMC1, CYP19A1, DDX3X, and TIMP3.
机构信息
Department of Obstetrics and Gynecology, University of Florida, Gainesville, Florida 32610, USA.
出版信息
J Clin Endocrinol Metab. 2012 Jul;97(7):E1316-26. doi: 10.1210/jc.2012-1018. Epub 2012 Apr 6.
CONTEXT
Evidence suggests that a number of microRNA (miRNA) are aberrantly expressed in endometrial disorders with potential posttranscriptional regulation of their specific target genes, including ovarian steroid receptors.
OBJECTIVES
Our objective was to assess the endometrial expression of miR-98 and miR-181a and their respective target genes, progesterone (P4) receptor membrane component 1 (PGRMC1) and P4 receptor (PGR).
DESIGN, SETTING, AND PATIENTS: We evaluated tissue expression and in vitro regulation at an academic university medical center in endometrial biopsies and endometrial tissues from follicular and luteal phases with and without exposure to hormonal therapies and grade I-III endometrial cancer (n = 52).
INTERVENTIONS
INTERVENTIONS included endometrial biopsies and in vitro transfection.
MAIN OUTCOME MEASURES
We evaluated expression and function of miR-98 and miR-181a.
RESULTS
Aberrant expression of miR-98 and miR-181a is associated with endometrial transition from normal into cancerous states, which to some extent is influenced by hormonal milieu, and exhibited an inverse relationship with PGMRC1 and PGR expression, respectively. Treatments of Ishikawa cells with 17β-estradiol, P4, or medroxyprogesterone acetate had limited effects on miR-98, miR-181a, and PGRMC1 expression, whereas 17β-estradiol treatment increased PGR expression. In Ishikawa cells, gain of function of miR-98 repressed PGRMC1 and CYP19A1, and miR-181a repressed PGR, DDX3X, and TIMP3 at mRNA and protein levels through direct interactions with their respective 3'-untranslated regions and CCNE1 through miR-181a-induced DDX3X repression, with miR-98 reducing the rate of cell proliferation as compared with controls.
CONCLUSION
miR-98 and miR-181a through their regulatory functions on PGRMC1, PGR, CYP19A1, TIMP3, and DDX3X expression may influence a wide range of endometrial cellular activities during normal menstrual cycle and transition into disease states, including endometrial cancer.
背景
有证据表明，许多 microRNA（miRNA）在子宫内膜疾病中表达异常，可能对其特定靶基因进行转录后调控，包括卵巢甾体激素受体。
目的
我们的目的是评估 miR-98 和 miR-181a 及其各自的靶基因孕激素（P4）受体膜成分 1（PGRMC1）和 P4 受体（PGR）在子宫内膜中的表达。
设计、地点和患者：我们在学术大学医学中心评估了子宫内膜活检和卵泡期和黄体期子宫内膜组织中的组织表达和体外调节，这些组织分别有无激素治疗和 I-III 级子宫内膜癌（n=52）。
干预措施
干预措施包括子宫内膜活检和体外转染。
主要观察指标
我们评估了 miR-98 和 miR-181a 的表达和功能。
结果
miR-98 和 miR-181a 的异常表达与子宫内膜从正常状态向癌变状态的转变有关，在某种程度上受激素环境的影响，并且与 PGMRC1 和 PGR 的表达呈负相关。用 17β-雌二醇、P4 或醋酸甲羟孕酮处理 Ishikawa 细胞对 miR-98、miR-181a 和 PGRMC1 的表达影响有限，而 17β-雌二醇处理增加了 PGR 的表达。在 Ishikawa 细胞中，miR-98 的功能获得抑制了 PGRMC1 和 CYP19A1 的表达，miR-181a 通过与各自的 3'-非翻译区直接相互作用以及通过 miR-181a 诱导的 DDX3X 抑制抑制 PGR、DDX3X 和 TIMP3 的表达，CCNE1 通过 miR-181a 诱导的 DDX3X 抑制，miR-98 与对照组相比降低了细胞增殖率。
结论
miR-98 和 miR-181a 通过对 PGRMC1、PGR、CYP19A1、TIMP3 和 DDX3X 表达的调节功能，可能影响正常月经周期和疾病状态（包括子宫内膜癌）中子宫内膜的广泛细胞活动。
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