Downregulated miR-195 Detected in Preeclamptic Placenta Affects Trophoblast Cell Invasion via Modulating ActRIIA Expression

Bai, Yang; Yang, Weiwei; Yang, Huixia; Liao, Qinping; Ye, Gang; Fu, Guodong; Ji, Lei; Xu, Peng; Wang, Hao; Li, Yuxia; Peng, Chun; Wang, Yanling

doi:10.1371/journal.pone.0038875

Cited by 99 publications

(89 citation statements)

References 40 publications

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“…The results presented here indicate that miR-195 and CUGBP1 interacted with the Igf2r mRNA via its 3=-UTR rather than the 5=-UTR and CR. These observations are consistent with other results indicating that miR-195 specifically binds to the 3=-UTRs of Cdk4, Cdk6, WEE1, MO25, ActRIIA, Stim1, and Sirt1 mRNAs to elicit its regulatory actions (17)(18)(19)(20)(21)(22)(23)(24). The use of reporters bearing partial transcripts spanning the Igf2r 5=-UTR, CR, or 3=-UTR with or without the predicted miR-195 binding site revealed that the Igf2r 3=-UTR contained the functional sequence through which miR-195 inhibited IGF2R translation.…”

Section: Discussionsupporting

confidence: 93%

“…It has been shown that miR-195 exerts its regulatory functions in different tissues by targeting multiple genes (14). miR-195 inhibits cell proliferation by reducing the levels of cyclin-dependent kinase 4 (CDK4), CCND1 (cyclin D1), CDK6, and WEE1 (19,20,22); promotes apoptosis by lowering SIRT1 abundance (23); and affects cell migration and cancer invasion by modulating expression of STIM1 (17) and ActRIIA (24). However, its potential role as a regulator of IGF receptor expression is unknown.…”

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confidence: 99%

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Cooperative Repression of Insulin-Like Growth Factor Type 2 Receptor Translation by MicroRNA 195 and RNA-Binding Protein CUGBP1

Zhang

Xiao

et al. 2017

Molecular and Cellular Biology

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Insulin-like growth factor type 2 (IGF2) receptor (IGF2R) recognizes mannose 6-phosphate-containing molecules and IGF2 and plays an important role in many pathophysiological processes, including gut mucosal adaptation. However, the mechanisms that control cellular IGF2R abundance are poorly known. MicroRNAs (miRNAs) and RNA-binding proteins (RBPs) critically regulate gene expression programs in mammalian cells by modulating the stability and translation of target mRNAs. Here we report that miRNA 195 (miR-195) and RBP CUG-binding protein 1 (CUGBP1) jointly regulate IGF2R expression at the posttranscriptional level in intestinal epithelial cells. Both miR-195 and CUGBP1 interacted with the 3= untranslated region (3=-UTR) of Igf2r mRNA, and the association of CUGBP1 with Igf2r mRNA enhanced miR-195 binding to Igf2r mRNA. Ectopically expressed CUGBP1 and miR-195 repressed IGF2R translation cooperatively without altering the stability of Igf2r mRNA. Importantly, the miR-195-and CUGBP1-repressed levels of cellular IGF2R led to a disruption in the structure of the trans-Golgi network. These findings indicate that IGF2R expression is controlled posttranscriptionally by two factors that associate with Igf2r mRNA and suggest that miR-195 and CUGBP1 dampen IGF signaling by inhibiting IGF2R translation.KEYWORDS insulin superfamily, posttranscriptional regulation, trans-Golgi network, intestinal epithelial cells, RNA-binding proteins, noncoding RNAs M ucosal regeneration/adaptation is an essential process in gut homeostasis and tightly regulated by numerous factors, including insulin-like growth factor type 1 (IGF1) and IGF2 (1, 2). Two structurally distinct types of receptors, the IGF1 receptor (IGF1R) and IGF2R, specifically interact with IGF1 and IGF2 as ligands and regulate diverse biological functions such as cell proliferation, differentiation, and apoptosis (3, 4). Like the insulin receptor, IGF1R is a heterotetrameric transmembrane receptor tyrosine kinase, and its activation results in autophosphorylation of tyrosine residues in the intracellular ␤-subunits, thus initiating the phosphatidylinositol 3-kinase (PI3) kinase/AKT and/or mitogen-activated protein (MAP) kinase signaling cascade (5). In contrast, IGF2R is a single-transmembrane-domain protein and binds IGF2 with greater affinity than IGF1, although it does not accept insulin as a ligand (4, 6). IGF2R also recognizes, via distinct sites, mannose-6-phosphate (M6P)-containing molecules and can therefore associate with other growth factors and cytokines (4). The majority of IGF2R is localized in the trans-Golgi network (TGN) and endosomal compartments and, to a lesser extent, on the cell surface (6). A subpopulation of the IGF2R on the plasma membrane regulates IGF2 internalization and various M6P-containing ligands for their

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Section: Discussionsupporting

confidence: 93%

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confidence: 99%

Cooperative Repression of Insulin-Like Growth Factor Type 2 Receptor Translation by MicroRNA 195 and RNA-Binding Protein CUGBP1

Zhang

Xiao

et al. 2017

Molecular and Cellular Biology

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“…39,40 However, it had growth-stimulating effect in HCT116 Dicere 14 Human placental trophoblast cells possess similar properties to tumor cells in terms of proliferation and invasion, although their behaviors are temporally and spatially restricted during pregnancy. 41 We did not find any influence of miR-210 on cell proliferation in HTR8/SVneo cells. Our finding of the inhibition on human trophoblast cell invasion by miR-210 was consistent with the recent reports by Zhang et al 24 and Anton et al 23 but were contradictory to the observations in endothelial cells 18 and renal carcinoma cells.…”

Section: Discussionmentioning

confidence: 53%

MicroRNA-210 Contributes to Preeclampsia by Downregulating Potassium Channel Modulatory Factor 1

Luo

Shao

et al. 2014

Hypertension

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C omplicating 7% to 10% of pregnancies, 1 preeclampsia, along with other hypertensive disorders of pregnancy, is a major contributor to maternal morbidity worldwide. 2,3Although abnormal placentation is thought to play a major role in the development of preeclampsia, the pathogenesis of this disorder is not clearly understood. 4 Defects of trophoblast cell function, such as reduced proliferation, 5 excessive apoptosis, 6 aberrant differentiation, 7 limited migration and invasion of the uterus, and poor remodeling of spiral arteries, 8,9 have been considered to be associated with preeclampsia. Nevertheless, the molecular mechanisms underlying the onset and progression of preeclampsia remain largely unknown.MicroRNAs are 22-to 24-nucleotide noncoding RNAs that regulate gene expression by seed sequence pairing with the 3′-untranslated region (UTR) of target mRNAs, leading to repressed translation or induced mRNA cleavage of the target genes. 10,11 MicroRNAs have been identified as essential mediators of numerous cellular processes, 12 potentially including the response to hypoxia. In particular, microRNA-210 (miR-210) is specifically induced by hypoxia-inducible factor-1α during hypoxia 13 and regulates many hypoxia response pathways, including cell survival, 14 angiogenesis, mitochondrial metabolism, 15 and DNA repair. 16 miR-210 can target and suppress a large number of genes, including the cell cycle regulator E2F transcription factor 3, 17 the receptor tyrosine kinase ligand ephrinA3, 18 the DNA repair protein RAD52, 19 and the iron-sulfur cluster assembly proteins 1/2. 15 Recent studies revealed that miR-210 was upregulated in patients with preeclampsia [20][21][22][23][24] and demonstrated that hypoxia-inducible miR-210 might participate in the occurrence of preeclampsia via the downregulation of ephrin-A3 and homeobox-A9. 24 The repressive effect of miR-210 on primary trophoblast cell invasion was also reported. 23 In addition, the study by us and others revealed that miR-210 could be a potential serum biomarker Abstract-Preeclampsia is a pregnancy-specific syndrome manifested by the onset of hypertension and proteinuria after the 20th week of gestation. Abnormal placenta development has been generally accepted as the initial cause of the disorder. Recently, microRNA-210 (miR-210) has been found to be upregulated in preeclamptic placentas compared with normal placentas, indicating a possible association of this small molecule with the placental pathology of preeclampsia. However, the function of miR-210 in the development of the placenta remains elusive. The aim of this study was to characterize the molecular mechanism of preeclampsia development by examining the role of miR-210. In this study, miR-210 and potassium channel modulatory factor 1 (KCMF1) expressions were compared in placentas from healthy pregnant individuals and patients with preeclampsia, and the role of miR-210 in trophoblast cell invasion via the downregulation of KCMF1 was investigated in the immortal trophoblast cell line HTR8/SVneo. Th...

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“…Therefore, miR-195 and miR-497 are potential therapeutic targets in many types of cancers (Furuta et al, 2013;Guo et al, 2012;Itesako et al, 2014;Li et al, 2011;Ozata et al, 2011). Additionally, miR-195 has been implicated in neurodevelopment (Ai et al, 2013;Liu et al, 2013;Zhu et al, 2012), placental pathogenesis (Bai et al, 2012;Hu et al, 2009) and glucose metabolism (Joglekar et al, 2007;Ortega et al, 2014), suggesting its importance in a range of biological processes.…”

Section: Introductionmentioning

confidence: 99%

The NF-ҡB modulated miR-195/497 inhibit myoblast proliferation by targeting Igf1r/Insr and cyclin genes

Wei

Zhang

Bai

et al. 2015

Journal of Cell Science

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MicroRNAs (miRNAs) play important roles in the development of skeletal muscle. In our previous study, expression of miR-195 and miR-497 were shown to be upregulated during muscle development in pigs. In this study, we investigated the roles of these two miRNAs in myogenesis and analyzed their transcriptional regulation. Our results showed that miR-195 and miR-497 were upregulated during muscle development and myoblast differentiation. Moreover, miR-195 and miR-497 inhibited proliferation but not differentiation in C2C12 cells. Further investigation revealed that Igf1r, Insr, Ccnd2 and Ccne1 were directly targeted by miR-195 and miR-497 in myoblasts. In addition, we confirmed that miR-195 and miR-497, which shared the similar expression profiling, were negatively regulated by nuclear factor κB (NF-κB) in both myoblasts and skeletal muscle tissue. Our data illustrate that the signaling pathway NF-κB-miR-195/497-Igf1r/InsrCcnd2/Ccne1 plays important roles in myogenesis. Our study provides novel evidence for the roles of miR-195 and miR-497 in muscle development.

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Downregulated miR-195 Detected in Preeclamptic Placenta Affects Trophoblast Cell Invasion via Modulating ActRIIA Expression

Cited by 99 publications

References 40 publications

Cooperative Repression of Insulin-Like Growth Factor Type 2 Receptor Translation by MicroRNA 195 and RNA-Binding Protein CUGBP1

Cooperative Repression of Insulin-Like Growth Factor Type 2 Receptor Translation by MicroRNA 195 and RNA-Binding Protein CUGBP1

MicroRNA-210 Contributes to Preeclampsia by Downregulating Potassium Channel Modulatory Factor 1

The NF-ҡB modulated miR-195/497 inhibit myoblast proliferation by targeting Igf1r/Insr and cyclin genes

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