Central Medical Journal of Obstetrics and Gynecology

Review Article Special Issue on Importance of 19 Prediction of Preeclampsia *Corresponding authors Hironori Takahashi, Department of Obstetrics and Gynecology, Jichi Medical University, 3311- miRNA Cluster in Pregnancy 1 Yakushiji, Shimotsuke, Tochigi 329-0498, JAPAN, Tel: +81-285-58-7376; Fax: +81-285-44-8505; E-mail: 1,2 1 1 Hironori Takahashi *, Akihide Ohkuchi , Rie Usui , Toshihiro Takizawa2, Shigeki Matsubara1 and Mitsuaki Suzuki1 Submitted: 26 April 2014 1Department of Obstetrics and Gynecology, Jichi Medical University, Japan Accepted: 09 June 2014 2Department of Molecular Medicine and Anatomy, Nippon Medical School, Japan Published: 10 June 2014 ISSN: 2333-6439 Abstract Copyright © 2014 Takahashi et al. microRNA (miRNA) has been focused on placental biology and pathogenesis. Chromosome 19 miRNA cluster (C19MC) miRNAs are known for placenta- and primate- OPEN ACCESS specific miRNAs. C19MC miRNAs are detected in maternal plasma even as early as the first trimester. To date, there are no miRNAs to be used as biomarkers of some disease Keywords in routine practice, although a few studies suggested C19MC miRNAs as biomarkers • Exosome of obstetrical diseases. C19MC miRNAs have been also reported as onco-miRs and • MicroRNA C19MC miRNAs target multiple in several kinds of malignancies. Two new • Preeclampsia insights into C19MC miRNAs in obstetrics have been recently reported. First, C19MC miRNAs induced viral resistance in non-trophoblast cells by autophagy. Second, fetal oncogenesis is associated with C19MC miRNAs. To clarify the pathogenesis of an obstetrical disease, roles of C19MC miRNAs need to be further investigated.

ABBREVIATIONS during pregnancy. Several miRNAs form miRNA clusters, which are localized in chromosome14q and 19q. Chromosome 19 miRNA miRNA: microRNA; RISC: RNA-Induced Silencing cluster (C19MC) and the chromosome 14 miRNA cluster (C14MC) Complex; C19MC: Chromosome 19 miRNA cluster; C14MC: have 46 and 52 miRNAs, respectively [6]. Of those, C19MC is a Chromosome 14 miRNA Cluster; HSD17β1: Hydroxysteroid17- beta Dehydrogenase 1; FGR: Fetal Growth Restriction; MEK1: the placenta [7-10]. Thus, it is reasonable to assume that C19MC Mitogen-activated kinase 1; FGFR1: Fibroblast Growth primate-specific cluster, and it is predominantly expressed in Factor Receptor 1; ETMRs: Embryonal Tumors with Multilayered diseases: especially its contribution to preeclampsia has now Rosettes; DNMT3B: DNA- Methyltransferase 3 Beta. becomemiRNAs amay matter be involved of topic. in Furthermore, the pathogenesis C19MC of primate-specificmiRNAs can be st trimester INTRODUCTION [11]. microRNA (miRNA) is a highly conserved, single-stranded, detected in maternal circulating blood flow from the 1 miRNA, to continue to be present in the circulating blood, 20-23-nucleotide RNA molecule. miRNA binds to target mRNA needs to be protected from degradation by RNAase. As described after miRNA is endocytosed by Argonaute protein to form an later, exosomes may contribute to it. Exosomes, approximately miRNA-complex, which is called the RNA-induced silencing 50-nm-sized microvesicles, contain mRNA and miRNAs, and thus complex (RISC). RISC represses or degrades the target miRNAs, being present in exosome without direct contact with expression. One important character of miRNA is: miRNA targets RNAase, remains un-degraded. Multiple exosomes are secreted multiple genes, and vice versa, i.e., a gene is targeted by multiple from trophoblasts, which are the functional cells of the placenta. miRNAs. Thus, miRNA, regulating the gene expression, mediates Circulating C19MC miRNAs are candidate markers of obstetrical/ multiple biological behaviors, such as invasion [1], proliferation placental diseases because, as described, they are solely derived from the placenta. In addition, recent papers revealed that 2,500 human miRNAs have been deposited in miRBase, which C19MC miRNAs were also associated with new roles such as constitutes[2], inflammation a database [3], andof miRNA. apoptosis New [4]. miRNAs To date, have approximately been rapidly fetal carcinogenesis, pluripotency, and viral resistance [12-14]. reported, which are added to this database, with the database In this paper, miRNAs in the placenta are reviewed, with special rapidly expanding. reference to C19MC miRNAs. The human placenta expresses numerous kinds of miRNA. C19MC miRNAs More than 800 miRNAsare reported to express in the human The human placenta expresses 3 miRNA clusters: C19MC, placenta [5]. The expression of miRNAs in the placenta changes C14MC, and miR-371-3 clusters. Of the 3 miRNA clusters, C19MC

Cite this article: Takahashi H, Ohkuchi A, Usui R, Takizawa T, Matsubara S, et al. (2014) Importance of Chromosome 19 miRNA Cluster in Pregnancy. Med J Obstet Gynecol 2(2): 1032. Takahashi et al. (2014) Email: Central and miR-371-3 clusters have orthologs only with orangutan, are activated by DNA methylation inhibitors, indicating that the gorilla, and chimpanzee [6]. The miR-371-3 cluster is composed region is under epigenetic control [16,18,19]. It was also reported of only miR-371, miR-372, and miR-373, whereas C19MC, located that C19MC miRNAs are onco-miR. A target gene of each C19MC in human chromosome 19 (19q13.42), includes 46 miRNA stranscribed from the -100-kb region [7,15]. The methylation miRNAs as biomarkers in obstetrical/placental of C19MC is regulated, namely, the (epigenetic) methylation miRNA has been clarified mainly in terms of oncology (Table 1). diseases patterns of the GC-rich promoter region in C19MC alter the expression of the region [16,17]. Experimentally, C19MC miRNAs The expressions of circulating miRNAs change in the

Table 1: Target genes of C19MC miRNAs. miRNA Cell Target Reference KSHV replication and miR-498 HEK293, HSV-1 infected body cavity-based lymphoma Yan (2013) [31] transcription activator Ovarian cancer cell line (OVCAR3, CAOV3, OV2008, A2780, 1,25-Dihydroxyvitamin D3 Kaslappan (2012) [32] C13), Ishikawa, HeLa, MCF-7 miR-512(-3p, -5p) BeWo PPP3R1 Kurashina (2013) [33] Breast cancer cell line (MDA-MB-231) CD44 Rutnam (2012) [34] Hepatocellular carcinoma cell line (HepG2) c-FLIP Chen (2010) [35] Gastric cancer cell line Mcl-1 Saito (2009) [36] miR-515(-3p, -5p) Breast cancer cell line SK1 Pinho (2013) [37] Breast cancer cell line, HEK-293 IGF-1R Gilam (2013) [38] miR-516a(-3p, -5p) Gastric cancer cell line (44As3) SULF1 Takei (2010) [39] Prostate cancer cell line (LNCaP) KLK10 White (2010) [40] miR-517a(-3p) Liver cancer cell line (YY8103) Pyk2 Liu (2013) [41] HEK293 TNIP1 Olarerin-George (2013) [42] miR-517c(-3p) HEK293 TNIP1 Olarerin-George (2013) [42] miR-518b NT2/D1, HEK-293 FOXN1 Kushwaha (2014) [43] Esophageal cancer cell line (Eca109, Ec9706, TE-1) rap1b Zhang (2012) [44] miR-518c(-3p, -5p) BeWo Ishibashi (2012) [24] miR-519b(-3p, -5p) Breast cancer cell line (T47D, MDA-MB-231) NK1 Navarro (2012) [45] HSD17β1 miR-519c(-3p, -5p) HEK293, Lung cancer cell line Cha (2010) [46] miR-519d(-3p, -5p) Hepatocellular carcinoma cell line (HepG2) PTEN, AKT3, CDKN1A/p21 Fornari (2012) [47] HIF1α Hepatocellular carcinoma cell line (QGY-7703) MKi67 Hou (2011) [48] miR-520a(-3p, -5p) 4T1 TUSC2P Rutnam (2014) [49] HEK-293 PIK3CA Arcaroli (2012) [50] miR-520b Hepatocellular carcinome cell line MEKK2, cyclinD1 Zhang (2012) [51] Breast cancer cell line (MCF-7,MDA-MB-231) HBXIP Hu (2012) [52] Breast cancer cell line (MCF-7, LM-MCF-7, MDA-MB-231) CD46 Cui (2010) [53] HeLa, Breast cancer cell line(MDA-MB-231), Melanoma cell MICA Yadav (2009) [54] line (A375), Colon cancer cell line (HCT116) Mazan-Mamczarz (2014) miR-520c(-3p, -5p) HeLa, Burkitt lymphoma cell line eIF4G [55] Hepatocellular carcinoma cell line Glypican-3 Miao (2013) [56] Breast cancer cell line CD44 Huang (2008) [1] Breast cancer cell line (MDA-MB-231, MCF-7) RELA, TGFBR2 Keklikoglou (2012) [57] miR-520d(-3p, -5p) Ovarian cancer cell line EphA2, EphB2 Nishimura (2013) [58] miR-520e Hepatocellular carcinoma cell line NIK Zhang (2012) [59] Breast cancer cell line (MCF-7, LM-MCF-7, MDA-MB-231) CD46 Cui (2010) [53] miR-520h Gastric cancer cell line (MKN45) HDAC1 Shen (2014) [60] miR-522(-3p, -5p) COS7 (HepG2, HEK-293) PLIN4 Richardson (2011) [61] miR-524(-3p, -5p) Glioblastoma cell line (LN229) Jagged-1, Hes-1 Chen (2012) [62] miR-525(-3p, -5p) Vascular endothelial cell line (EA.hy926) ARRB1, TXN1, HSPA9 Kraemer (2013) [63] HEK-293 VPAC1 Cocco (2010) [64] HEK-293 PIK3CA Arcaroli (2012) [50] KSHV: Kaposi’s sarcoma-associated herpes virus; HSV: Herpes simplex virus; c-FLIP: FLICE-like inhibitory protein; SK-1: Sphingosine kinase 1; SULF1: KLK10: Kallikrein-ralated peptidase 10; Extracellular sulfatase 1; TNIP1; TNFAIP3 interacting protein 1; FOXN1:Forkhead bozproteing N1; PIK3CA: NK1: Neurokinin 1; HIF1: Hypoxia inducible factor 1; TUSC2: Tumor suppressor candidate 2; TUSC2P: Tumor suppressor candidate 2 pseudogene: PIK3CA: Phosphoinositide 3 kinase; HBXIP: Hepatitis B X-interacting protein; MICA: MHC class l-related chain A; eIF4Gll: Eukaryotic translation initiation factor 4, gamma; HDAC1: Histone deacetylase 1

Med J Obstet Gynecol 2(2): 1032 (2014) 2/5 Takahashi et al. (2014) Email: Central maternal blood during pregnancy [11]. Several studies have hand, another author showed that miR-154 is down-regulated in reported the relationships between circulating miRNAs and the preeclamptic placenta [30]. We assume that one of the key obstetrical and/or placental diseases [20-23]. Apart from pointsfor these discrepancies may be the different in miRNA C19MC miRNAs, miR-210 has been one of the most well-known measurement, i.e., the standardization of miRNA for miRNA. To miRNAs, and is associated with hypoxia. A recent study involved standardize miRNAs, several internal controls such as RNU6, high-throughput sequencing and quantitative PCR-based RNU44, S18, miR-16, and let-7d are usually employed. However, array of normal and preeclamptic placenta [24]. As a result, it remains unknown whether these internal controls are validated miR-210 was up-regulated in both analyses. Furthermore, the in maternal plasma. New insights into C19MC miRNAs instudy preeclamptic revealed maternal that miR-210 serum even targeted before hydroxysteroid17-β the appearance of Recently, two novel insights into C19MC miRNAs were clinicaldehydrogenase manifestation 1 (HSD17β1). of preeclampsia HSD17β1 in awas prospective down-regulated cohort published. Firstly, a study showed that C19MC miRNAs induced viral resistance in non-trophoblast cells by autophagy [13]. The associated gene [25]. miR-424 has also attracted attention authors focused on culture supernatants of full-term trophoblasts. recently.study. miR-210 miRNA also expressions targets HIF-1α, at pre-labor which is known and delivery as a hypoxia- were analyzed [26]. From pre-labor toward delivery, miR-210, -424, trophoblastic cell lines using only the trophoblast-derived -199a, and -20b increased by 4.2-fold 2.7-fold 2.6-fold and 2.3- supernatant.The efficacy of The virus supernatant infection significantly includes numerous decreased exosome- in non- fold, respectively. Furthermore, hypoxia-related miRNAs (miR- containing C19MC miRNAs. Then, the authors hypothesized that the recipient cells gained viral resistance by taking in exosome-containing C19MC miRNAs. To clarify the mechanism, 424, -21, -199a, and -20b), which are associated with HIF-1α, [26]. Indeed, miR-424 and miR-21 were up-regulated in cases they focused on autophagy, which induces the degradation significantly increased in pregnancies complicated by severe FGR of microbial invaders. They discovered that autophagosomes Anotherof absent study diastolic revealed umbilical that arterial miR-424 flow expression (a sign inof placental insufficiency) compared with those showing normal flow [26]. conditioned medium (containing primary trophoblast-derived exosomes)were significantly compared present with in recipient exosome-depleted cells supplemented conditioned with receptortissue with 1 (FGFR1) FGR is are significantly inversely decreased increased, [27]. whereas Another mitogen- author Furthermore, they suppressed autophagy by treatment with provedactivated that protein MEK1 kinase and FGFR1 1 (MEK1) are target and fibroblast genes of miR-424growth factor [28]. 3-methyladenine,medium, which an was inhibitor confirmed of autophagosome by electron formation, micrographs. and Taken together, miR-210 and miR-424 seem to be induced in siBeclin 1, a key factor in autophagic induction. placental hypoxia. Secondly, fetal oncogenesis is associated with C19MC miRNAs With regard to C19MC miRNAs in maternal blood, C19MC [14]. C19MC miRNAs may be associated with human primate miRNAs are also involved in obstetrical/placental diseases (Table 2). Some studies showed that C19MC miRNAs changed evolution [19]. Of those, miR-498 expression can be detected in obstetrical/placental diseases, such as preeclampsia and fetal in the fetal brain at 20 weeks [17]. Kleinman et al. focused on growth restriction (Table 2). However, there is no evidence embryonal tumors with multilayered rosettes (ETMRs), which to support using circulating miRNAs as diagnostic markers. is a disease associated with a poor prognosis. ETMR is known For instance, miR-154 in placental tissue is up-regulated in for its characteristic DNA methylation and high-level expression preeclampsia with small-for-gestational age [29]. On the other of C19MC miRNAs. They conducted copy number variation analysis of exome sequencing in 12 ETMR samples. Surprisingly, Table 2: C19MC miRNA expression in maternal plasma. C19MC miRNAs were highly expressed by fusing TTYH1 in allthe Obstetrical samples. The fusion of C19MC miRNAs and TTYH1 increases miRNA Reference disease miR-520d-5p, miR-526a NA Gilad (2008) [65] normalbrain-specific fetal growth. DNA-methyltransferase The C19MC miRNAs 3 beta targeted (DNMT3B), RBL2, which miR-517, miR-518 NA Luo (2009) [9] is expressed a suppressor only of in DNMT3B.the first weeks Thus, of the neural authors tube development concluded that in miR-515-3p, miR-517a, miR- Miura (2010) NA DNMT3B over expression by suppressing RBL2 might alter DNA 517c, miR-518b, miR-526b [11] methylation and the programming of neural tube development. miR-516-5p, miR-517*, miR- Kotlabova (2011) 518b, miR-520a*, miR-520h, NA CONCLUSION [66] miR-525, miR-526a miR-517a, miR-518b, miR-518e, Donker (2012) FGR There are strong reasons to use C19MC miRNAs as novel miR-519d, miR-525-5p [67] biomarkersC19MC miRNAs in obstetrics, are primate- although and organ-specific, several technical as described. problems Ishibashi (2012) miR-518c Preeclampsia need to overcome. Also, clarifying the roles of C19MC miRNAs [24] may be a key to the pathologic elucidation of obstetrical diseases miR-516-5p, miR-517*, miR- Hromadnikova Preeclampsia including fetal abnormalities. Target mRNAs targeted by C19MC 520a*, miR-525, miR-526a (2013) [21] miRNA shave been poorly validated. Targetting C19MC miRNAs miR-518b, miR-1323, miR-520h, Higashijima FGR miR-519d (2013) [22] can lead to new diagnostic and/or therapeutic options. Complete Hasegawa (2013) REFERENCES miR-520f, miR-520b, miR-520c-3p hydatidiform [23] mole 1. Huang Q, Gumireddy K, Schrier M, le Sage C, Nagel R, Nair S, et al. The FGR: Fetal growth restriction; NA: Not applicable microRNAs miR-373 and miR-520c promote tumour invasion and

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