title: miR-210 targets iron-sulfur cluster scaffold homologue in human trophoblast cell lines: siderosis of interstitial trophoblasts as a novel pathology of preterm preeclampsia and small-for-gestational-age pregnancies.
abstract: 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.
authors.affiliation: Department of Health and Human Services, Perinatology Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Deug-Chan
authors.initials: DC
authors.lastname: Lee
authors.forename: Roberto
authors.initials: R
authors.lastname: Romero
authors.forename: Jung-Sun
authors.initials: JS
authors.lastname: Kim
authors.forename: Adi L
authors.initials: AL
authors.lastname: Tarca
authors.forename: Daniel
authors.initials: D
authors.lastname: Montenegro
authors.forename: Beth L
authors.initials: BL
authors.lastname: Pineles
authors.forename: Ernest
authors.initials: E
authors.lastname: Kim
authors.forename: JoonHo
authors.initials: J
authors.lastname: Lee
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Sorin
authors.initials: S
authors.lastname: Draghici
authors.forename: Pooja
authors.initials: P
authors.lastname: Mittal
authors.forename: Juan Pedro
authors.initials: JP
authors.lastname: Kusanovic
authors.forename: Tinnakorn
authors.initials: T
authors.lastname: Chaiworapongsa
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Hassan
authors.forename: Chong Jai
authors.initials: CJ
authors.lastname: Kim
mesh_terms: D020413:3' Untranslated Regions; D000293:Adolescent; D000328:Adult; D002460:Cell Line; D045744:Cell Line, Tumor; D002822:Choriocarcinoma / Q000378:metabolism; D005260:Female; D006801:Humans; D000860:Hypoxia; D017403:In Situ Hybridization; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D010920:Placenta / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000378:metabolism; D011247:Pregnancy; D034622:RNA Interference; D012806:Siderosis / Q000473:pathology; D014327:Trophoblasts / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; C506160:ISCU protein, human; D007506:Iron-Sulfur Proteins; C543800:MIRN210 microRNA, human; D035683:MicroRNAs