MicroRNA‐590‐3p inhibits trophoblast‐dependent maternal spiral artery remodeling by repressing low‐density lipoprotein receptor‐related protein 6

Zhang, Yinghong; Pan, Xian-Zhen; Yu, Xiaoyan; Li, Lei; Qu, Hongmei; Li, Shuhong

doi:10.1002/mgg3.491

Cited by 12 publications

(10 citation statements)

References 41 publications

(48 reference statements)

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“…It is well known that LRP6 plays an essential role in the growth and invasion of trophoblasts . Low expression levels of LRP6 inhibited the migration and proliferation of trophoblasts, and several reports demonstrated that LRP6 was highly associated with trophoblast function via the canonical Wnt/β‐catenin pathway . However, whether LRP6 exerts this function through autophagy has never been illustrated until now.…”

Section: Introductionmentioning

confidence: 99%

LRP6 regulates Rab7‐mediated autophagy through the Wnt/β‐catenin pathway to modulate trophoblast cell migration and invasion

Peng

Zhou

et al. 2019

J of Cellular Biochemistry

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Pre‐eclampsia is a common complication during pregnancy; however, the underlying mechanisms of the crosstalk between low‐density lipoprotein receptor‐related protein 6 (LRP6) and autophagy in trophoblast cells are still not fully explored. Messenger RNA (mRNA) and protein levels of LRP6, beclin 1, Unc‐51‐like autophagy activating kinase 1 (ULK1), p62, vimentin, matrix metallopeptidase‐9 (MMP‐9), β‐catenin, c‐Myc, and Rab7, as well as the ratio of LC3‐II/LC3‐I, were analysed by quantitative real‐time polymerase chain reaction or Western blot analysis, respectively. An MTT assay was used to measure cell growth, and transwell and wound healing assays were carried out to evaluate the invasion and migration abilities of the trophoblasts used. An immunofluorescence assay was used to measure LC3. The mRFP‐GFP‐LC3 tandem fluorescence assay was applied to detect autophagic flow. LRP6 overexpression was achieved by constructing pcDNA3.1‐LRP6 vectors. LRP6 was expressed at low levels in HTR‐8/SVneo cells under hypoxia/reoxygenation (H/R) conditions. H/R inhibited the activation of autophagy. LRP6 overexpression promoted cell proliferation and activated autophagy, which led to the upregulation of beclin 1 and ULK1, as well as the ratio of LC3‐II/LC3‐I and the downregulation of p62. Furthermore, LRP6 overexpression elevated the migration and invasion abilities of the indicated cells and increased vimentin and MMP‐9 expression levels. Furthermore, LRP6 upregulated Rab7 and activated autophagy through the Wnt/β‐catenin pathway. The late autophagy inhibitor bafilomycin A1 (Baf‐A1) and the Wnt/β‐catenin pathway inhibitor PKF115‐584 reversed the effects of LRP6 on trophoblast autophagy, migration and invasion. LRP6 promotes Rab7‐mediated autophagy by activating the Wnt/β‐catenin pathway, which leads to increasing migration and invasion of trophoblast cells. Our study paves a new avenue for clinical treatment, and LRP6 may serve as an essential target in pre‐eclampsia.

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Section: Introductionmentioning

confidence: 99%

LRP6 regulates Rab7‐mediated autophagy through the Wnt/β‐catenin pathway to modulate trophoblast cell migration and invasion

Peng

Zhou

et al. 2019

J of Cellular Biochemistry

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“…LRP6 was reported to be involved in the proliferation, migration and invasion of trophoblast cells via miR-346 [ 28 ]. Notably, miR-590-3p might inhibit trophoblast-dependent maternal spiral artery remodeling by regulating both trophoblast invasion and endovascular formation through the repression of LRP6 [ 29 ]. Based on the results, LRP6 might be regulated by different miRNAs that changing trophoblast function.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-513c-5p is involved in the pathogenesis of preeclampsia by regulating of low-density lipoprotein receptor-associated protein 6

Zhou

Zhang

et al. 2021

BMC Pregnancy Childbirth

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Background Preeclampsia (PE) is a major cause of maternal and perinatal morbidity and mortality. Studies on the role of microRNAs (miRNAs), in the pathogenesis of PE through their effects on trophoblast function have been reported, but roles for some miRNAs including miR-513c-5p, have not been identified. We aimed to evaluate potential miRNA candidates that regulate the LRP6 mRNAand to elucidate the possible mechanism in PE. Potential miRNAs were selected by bioinformatics analysis, PCR of placenta tissues and dual luciferase reporter assay of HTR-8/SVneo cells. Methods A bioinformatics analysis (Gene Expression Omnibus, GEO; miRWalk) was performed to screen the possible miRNAs that participate in the pathology of PE. Placentas from patients with PE and women with a normal pregnancy were collected to detect the expression of predicted miRNAs by RT-qPCR. A dual luciferase reporter assay was used to test the binding of the potential miRNAs to LRP6. The effects of miR-513c-5p on the biological functions of HTR-8/SVneo cells were further evaluated by performing EdU staining, flow cytometry, wound healing assays and Transwell assays. Results GEO and miRWalk predicted 16 miRNAs that might target LRP6. Hsa-miR-371a-5p, hsa-miR-513c-5p, hsa-miR-126-3p, hsa-miR-145-5p, hsa-miR-193b-5p and hsa-miR-296-5p were 6 miRNAs upregulated in the PE placenta. LRP6 was downregulated in patients with PE compared to normal women. miR-513c-5p mimics inhibited LRP6 expression in HTR-8/SVneo cells, and LRP6 is the target gene of miR-513c-5p. miR-513c-5p mimics also inhibited invasion, migration and proliferation of HTR-8/SVneo cells but promoted their apoptosis. Conclusions Our study reveals that overexpression of placenta miR-513c-5p is involved in PE by regulating the biological functions of trophoblasts through the inhibition of LRP6.

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“…MiR‐590‐3p down‐regulated the expressions of MMPs in HTR‐8/SVneo cells through suppressing LRP6 39 . In this present study, the result showed that miR‐95‐5p bind to the 3′ UTR of LRP6, and the expression of miR‐95‐5p was evidently up‐regulated in PE tissues and trophoblast cell lines, suggesting that miR‐95‐5p may be involved in the invasion process of trophoblast cells and affect the occurrence and progress of PE.…”

Section: Discussionmentioning

confidence: 99%

MiR‐95‐5p involves in the migration and invasion of trophoblast cells by targeting low density lipoprotein receptor‐related protein 6

Xiao

et al. 2020

J of Obstet and Gynaecol

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AimsLow density lipoprotein receptor‐related protein 6 (LRP6) has been demonstrated to control trophoblast cell invasion, but its regulatory gene remains undefined. In this study, microRNA (miR) regulating LRP6 were explored to elucidate the potential mechanism of preeclampsia (PE).MethodsFirstly, the expression of LRP6 in PE tissues was detected by immunohistochemical staining and quantitative real‐time polymerase chain reaction (qRT‐PCR) assay. Prediction software predicted that LRP6 might be the target gene of miR‐95‐5p, and verified by double‐luciferase reporter analysis. qRT‐PCR assay measured the expression of miR‐95‐5p in PE tissues and trophoblast cell lines. Then, we transfected miR‐95‐5p mimic, inhibitor, LRP6, or mimic plus LRP6 into trophoblast cell lines, and analyzed their influences on cell migration and invasion by wound healing and Transwell experiments. The expressions of matrix metalloproteinase (MMP)‐2, MMP‐9 and tissue inhibitors of metalloproteinase (TIMP)‐1 in transfected cells were examined by western blot (WB) analysis.ResultsLRP6 was low‐expressed in PE tissues, while miR‐95‐5p expression was high‐expressed. MiR‐95‐5p negatively regulated the LRP6 expression in trophoblast cells. Both up‐regulated LRP6 and down‐regulated miR‐95‐5p can not only promote the migration and invasion of trophoblast cells, but also raised the expressions of MMP‐2 and MMP‐9 and inhibited the expression of TIMP‐1. The over‐expression of miR‐95‐5p suppressed the metastasis of trophoblast cells and rescued LRP6‐induced increase of MMP‐2 and MMP‐9 and reduction of TIMP‐1.ConclusionMiR‐95‐5p involved in the migration and invasion of trophoblast cells by targeting LRP6, which might be a potential therapeutic target for PE.

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MicroRNA‐590‐3p inhibits trophoblast‐dependent maternal spiral artery remodeling by repressing low‐density lipoprotein receptor‐related protein 6

Cited by 12 publications

References 41 publications

LRP6 regulates Rab7‐mediated autophagy through the Wnt/β‐catenin pathway to modulate trophoblast cell migration and invasion

LRP6 regulates Rab7‐mediated autophagy through the Wnt/β‐catenin pathway to modulate trophoblast cell migration and invasion

MicroRNA-513c-5p is involved in the pathogenesis of preeclampsia by regulating of low-density lipoprotein receptor-associated protein 6

MiR‐95‐5p involves in the migration and invasion of trophoblast cells by targeting low density lipoprotein receptor‐related protein 6

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