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Upregulation of PUM1 Expression in Preeclampsia Impairs Trophoblast Invasion by Negatively Regulating the Expression of the lncRNA HOTAIR.

ABSTRACT: Pumilio (PUM) proteins are members of a highly conserved RNA-binding protein family that posttranscriptionally regulate gene expression in many organisms. However, their roles in the placenta are unclear. In the present study, we report the requirement for the PUM homolog 1 (PUM1) gene in preeclampsia (PE). Immunofluorescence and immunohistochemical data showed that PUM1 was highly expressed in human placental villi from women with PE compared to healthy controls (HCs). Further, PUM1 overexpression repressed, and knockdown enhanced, the invasion and proliferation of trophoblasts. Interestingly, PUM1 knockdown promoted trophoblast invasion in a villous explant culture model, while PUM1 overexpression repressed these effects. Furthermore, lncRNA transcriptome sequencing coupled with RNA immunoprecipitation (RIP) revealed that PUM1 inhibits trophoblast invasion in PE by downregulating the expression of lncRNA HOTAIR. Moreover, PUM1 regulates HOTAIR expression via a posttranscriptional mechanism. Using RNA-protein pull-down and mRNA stability assays, we identified PUM1 as a specific binding partner that decreased the half-life of HOTAIR and lowered the steady-state level of HOTAIR expression, suggesting a novel posttranscriptional regulatory mechanism. Collectively, these findings identified a novel RNA regulatory mechanism, revealing a new pathway governing the regulation of PUM1/HOTAIR in trophoblast invasion in the pathogenesis of PE.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC7001091 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Upregulation of PUM1 Expression in Preeclampsia Impairs Trophoblast Invasion by Negatively Regulating the Expression of the lncRNA HOTAIR.

Zhang Yan Y He Xiao-Ying XY Qin Shi S Mo Hui-Qin HQ Li Xiao X Wu Fan F Zhang Jing J Li Xing X Mao Lin L Peng Ya-Qing YQ Guo Yu-Na YN Lin Yi Y Tian Fu-Ju FJ

Molecular therapy : the journal of the American Society of Gene Therapy 20191206 2

Pumilio (PUM) proteins are members of a highly conserved RNA-binding protein family that posttranscriptionally regulate gene expression in many organisms. However, their roles in the placenta are unclear. In the present study, we report the requirement for the PUM homolog 1 (PUM1) gene in preeclampsia (PE). Immunofluorescence and immunohistochemical data showed that PUM1 was highly expressed in human placental villi from women with PE compared to healthy controls (HCs). Further, PUM1 overexpress ...[more]

PMID: 31862314

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Project description:Preeclampsia (PE) is a common cause of maternal morbidity, characterized by impaired trophoblast invasion and spiral artery transformation resulting in progressive uteroplacental hypoxia. Given the primary role of LIN28A and LIN28B in modulating cell metabolism, differentiation, and invasion, we hypothesized that LIN28A and/or LIN28B regulates trophoblast differentiation and invasion, and that its dysregulation may contribute to PE. Here we show that LIN28B is expressed ∼1300-fold higher than LIN28A in human term placenta and is the predominant paralog expressed in primary human trophoblast cultures. The expression of LIN28B mRNA and protein levels are significantly reduced in gestational age-matched preeclamptic vs. normal placentas, whereas LIN28A expression is not different. First trimester human placental sections displayed stronger LIN28B immunoreactivity in extravillous (invasive) cytotrophoblasts and syncytial sprouts vs. villous trophoblasts. LIN28B overexpression increased HTR8 cell proliferation, migration, and invasion, whereas LIN28B knockdown in JEG3 cells reduced cell proliferation. Moreover, LIN28B knockdown in JEG3 cells suppressed syncytin 1 (SYN-1), apelin receptor early endogenous ligand (ELABELA), and the chromosome 19 microRNA cluster, and increased mRNA expression of ITGβ4 and TNF-α. Incubation of BeWo and JEG3 cells under hypoxia significantly decreased expression of LIN28B and LIN28A, SYN-1, and ELABELA, whereas TNF-α is increased. These results provide the first evidence that LIN28B is the predominant paralog in human placenta and that decreased LIN28B may play a role in PE by reducing trophoblast invasion and syncytialization, and by promoting inflammation.-Canfield, J., Arlier, S., Mong, E. F., Lockhart, J., VanWye, J., Guzeloglu-Kayisli, O., Schatz, F., Magness, R. R., Lockwood, C. J., Tsibris, J. C. M., Kayisli, U. A., Totary-Jain, H. Decreased LIN28B in preeclampsia impairs human trophoblast differentiation and migration.

Project description:BackgroundLong non-coding RNAs (lncRNAs) have emerged as a new and crucial layer of gene regulation in recent years and regulate various biological processes such as carcinogenesis and metastasis. LncRNA HOTAIR, an oncogenic lncRNA, is involved in human tumorigenesis and dysregulated in cervical cancer. Megakaryoblastic leukemia 1 (MKL1), as a transcription coactivity factor, involved in cancer metastasis and cell differentiation. However, the precise mechanism of biological roles of HOTAIR and MKL1 in cancer cells remain unclear.MethodsThe expression levels of HOTAIR and MKL1 were measured by quantitative PCR (qPCR), immunoblotting, in situ hybridization (ISH) and immunohistochemistry (IHC). Wound-healing and transwell assays were used to examine the invasive abilities of HeLa cells. Luciferase reporter assays and CHIP were used to determine how MKL1 regulates HOTAIR. Tissue microarray and immunohistochemical staining were used to assess the correlation between HOTAIR and MKL1 in Cervical cancer tissues in vivo.ResultIn this study, we have identified that MKL1 had a role in the induction of migration and invasion in cervical cancer cells. Moreover, the expression level of MKL1, as the targeting gene of miR206, was decreased after HOTAIR inhibition in HeLa cells. Agreement with it, Highly level of MKL1 correlation with HOTAIR is validated in cervical cancer tissues. Importantly, HOTAIR is observed to participate in the silencing of miR206 expression. Interestingly, HOTAIR inhibition could also accelerate the expression of MKL1 in cytoplasm. What is more, MKL1 can activate the transcription of HOTAIR through binding the CArG box in the promoter of HOTAIR.ConclusionThese elucidates that the phenotypic effects of migration and invasion observed after HOTAIR inhibition, at least in part, through the regulation of MKL1 via inhibition of miR206 expression in HeLa cells. These data indicate the existence of a positive feedback loop between HOTAIR and MKL1. Together, these findings suggest that MKL1 is an important player in the functions of HOTAIR in the migration and invasion of cancer cells.

Dataset Information

Upregulation of PUM1 Expression in Preeclampsia Impairs Trophoblast Invasion by Negatively Regulating the Expression of the lncRNA HOTAIR.

Publications

Upregulation of PUM1 Expression in Preeclampsia Impairs Trophoblast Invasion by Negatively Regulating the Expression of the lncRNA HOTAIR.

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