Department of Health and Human Services, Perinatology Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Am J Pathol. 2011 Aug;179(2):590-602. doi: 10.1016/j.ajpath.2011.04.035.
This study was performed to assess the biological significance of miR-210 in preeclampsia and small-for-gestational-age (SGA) pregnancies. Placental miR-210 expression was evaluated by quantitative RT-PCR (RT-qPCR) in the following groups: i) appropriate-for-gestational-age pregnancies (n = 72), ii) preeclampsia (n = 52), iii) SGA (n = 66), and iv)preeclampsia with SGA (n = 31). The effects of hypoxia (1% O(2)) on miR-210 and iron-sulfur cluster scaffold homologue (ISCU) expressions and miR-210 binding to ISCU 3' UTR were examined in Swan 71 and BeWo cell lines. Perls' reaction (n = 229) and electron microscopy (n = 3) were conducted to verify siderosis of trophoblasts. miR-210 expression was increased in preeclampsia and SGA cases and was decreased with birth weight and gestational age. In both cell lines, miR-210 was induced by hypoxia, whereas ISCU expression was decreased. The luciferase assay confirmed miR-210 binding to ISCU mRNA 3' UTR. RNA interference knockdown of ISCU expression in Swan 71, but not in BeWo, cells resulted in autophagosomal and siderosomal iron accumulation and a fourfold decrease of Matrigel invasion (P = 0.004). Placental ISCU expression was decreased in preeclampsia (P = 0.002) and SGA (P = 0.002) cases. Furthermore, hemosiderin-laden trophoblasts were more frequent in the placental bed of preterm preeclampsia and/or SGA births than in control cases (48.7% versus 17.9%; P = 0.004). Siderosis of interstitial trophoblasts is a novel pathological feature of preeclampsia and SGA. The findings herein suggest that ISCU down-regulation by miR-210 perturbing trophoblast iron metabolism is associated with defective placentation.
这项研究旨在评估 miR-210 在子痫前期和小于胎龄儿（SGA）妊娠中的生物学意义。通过定量 RT-PCR（RT-qPCR）评估以下组别的胎盘 miR-210 表达：i）适当胎龄妊娠（n=72），ii）子痫前期（n=52），iii）SGA（n=66），和 iv）子痫前期合并 SGA（n=31）。在 Swan 71 和 BeWo 细胞系中，研究了缺氧（1% O2）对 miR-210 和铁硫簇支架同源物（ISCU）表达的影响，以及 miR-210 与 ISCU 3'UTR 的结合。对 229 例 Perls 反应（n=229）和 3 例电子显微镜检查（n=3）进行了验证，以验证滋养层细胞的含铁血黄素沉着。miR-210 在子痫前期和 SGA 病例中表达增加，且与出生体重和胎龄呈负相关。在这两种细胞系中，miR-210 均由缺氧诱导，而 ISCU 表达则下降。荧光素酶测定证实 miR-210 与 ISCU mRNA 3'UTR 结合。在 Swan 71 细胞中，而非 BeWo 细胞中，ISCU 表达的 RNA 干扰敲低导致自噬体和 siderosome 铁积累，并使 Matrigel 侵袭减少四倍（P=0.004）。子痫前期（P=0.002）和 SGA（P=0.002）病例中的胎盘 ISCU 表达下降。此外，与对照组相比，早产子痫前期和/或 SGA 分娩的胎盘床中富含含铁血黄素的滋养层细胞更为常见（48.7%比 17.9%；P=0.004）。间质滋养层细胞的含铁血黄素沉着是子痫前期和 SGA 的一种新的病理特征。这些发现表明，miR-210 通过下调 ISCU 扰乱滋养细胞铁代谢与胎盘功能不全有关。
