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NRP1 and MMP9 are dual targets of RNA‐binding protein QKI5 to alter VEGF‐R/ NRP1 signalling in trophoblasts in preeclampsia
Preeclampsia (PE) is characterized by placental ischemia and hypoxia, resulting in abnormal casting of the uterine spiral artery, which is mainly caused by insufficient trophoblastic cell infiltration. A reduction in levels of growth factor‐based signalling via Neuropilin‐1 (NRP1) has been shown to...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184681/ https://www.ncbi.nlm.nih.gov/pubmed/33942999 http://dx.doi.org/10.1111/jcmm.16580 |
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author | Yang, Xingyu Chen, Dan He, Biwei Cheng, Weiwei |
author_facet | Yang, Xingyu Chen, Dan He, Biwei Cheng, Weiwei |
author_sort | Yang, Xingyu |
collection | PubMed |
description | Preeclampsia (PE) is characterized by placental ischemia and hypoxia, resulting in abnormal casting of the uterine spiral artery, which is mainly caused by insufficient trophoblastic cell infiltration. A reduction in levels of growth factor‐based signalling via Neuropilin‐1 (NRP1) has been shown to contribute to dysfunctional trophoblast development. In this study, we showed that the RNA‐binding protein, QKI5, regulated NRP1 expression and significantly improved trophoblast proliferation in vitro and in vivo. QKI5 and NRP1 expressions were significantly reduced in human PE placentas and in trophoblasts during hypoxia. Overexpression of these factors significantly improved cell proliferation and migration in vitro, in contrast to a decrease upon siRNA knockdown of QKI5 and NRP1 in HTR‐8/SVneo cells. Using RIP and RNA pull‐down assays, we further showed that QKI5 directly interacted with the 3'‐UTR region of NRP1, to mediate cell proliferation and migration via matrix metalloprotease‐9. Further, similar to NRP1, QKI5 also targets matrix metalloproteinase 9 (MMP9) involved in secretion of growth factors and its effects can be counteracted by NRP1 overexpression. In vivo studies using a PE mouse model revealed that QKI5 overexpression alleviated PE‐related symptoms such as elevated blood pressure and proteinuria. Taken together, we found that QKI5 was a novel regulator, of VEGF‐R/NRP1 signalling pathway functioning in trophoblast proliferation and migration, resulting in major contributors to the pathogenesis of PE. While careful evaluation of the broad implications of QKI5 expression is still necessary, this study identified QKI5 as a promising target for treatment strategies in acute PE patients. |
format | Online Article Text |
id | pubmed-8184681 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-81846812021-06-15 NRP1 and MMP9 are dual targets of RNA‐binding protein QKI5 to alter VEGF‐R/ NRP1 signalling in trophoblasts in preeclampsia Yang, Xingyu Chen, Dan He, Biwei Cheng, Weiwei J Cell Mol Med Original Articles Preeclampsia (PE) is characterized by placental ischemia and hypoxia, resulting in abnormal casting of the uterine spiral artery, which is mainly caused by insufficient trophoblastic cell infiltration. A reduction in levels of growth factor‐based signalling via Neuropilin‐1 (NRP1) has been shown to contribute to dysfunctional trophoblast development. In this study, we showed that the RNA‐binding protein, QKI5, regulated NRP1 expression and significantly improved trophoblast proliferation in vitro and in vivo. QKI5 and NRP1 expressions were significantly reduced in human PE placentas and in trophoblasts during hypoxia. Overexpression of these factors significantly improved cell proliferation and migration in vitro, in contrast to a decrease upon siRNA knockdown of QKI5 and NRP1 in HTR‐8/SVneo cells. Using RIP and RNA pull‐down assays, we further showed that QKI5 directly interacted with the 3'‐UTR region of NRP1, to mediate cell proliferation and migration via matrix metalloprotease‐9. Further, similar to NRP1, QKI5 also targets matrix metalloproteinase 9 (MMP9) involved in secretion of growth factors and its effects can be counteracted by NRP1 overexpression. In vivo studies using a PE mouse model revealed that QKI5 overexpression alleviated PE‐related symptoms such as elevated blood pressure and proteinuria. Taken together, we found that QKI5 was a novel regulator, of VEGF‐R/NRP1 signalling pathway functioning in trophoblast proliferation and migration, resulting in major contributors to the pathogenesis of PE. While careful evaluation of the broad implications of QKI5 expression is still necessary, this study identified QKI5 as a promising target for treatment strategies in acute PE patients. John Wiley and Sons Inc. 2021-05-04 2021-06 /pmc/articles/PMC8184681/ /pubmed/33942999 http://dx.doi.org/10.1111/jcmm.16580 Text en © 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Yang, Xingyu Chen, Dan He, Biwei Cheng, Weiwei NRP1 and MMP9 are dual targets of RNA‐binding protein QKI5 to alter VEGF‐R/ NRP1 signalling in trophoblasts in preeclampsia |
title | NRP1 and MMP9 are dual targets of RNA‐binding protein QKI5 to alter VEGF‐R/ NRP1 signalling in trophoblasts in preeclampsia |
title_full | NRP1 and MMP9 are dual targets of RNA‐binding protein QKI5 to alter VEGF‐R/ NRP1 signalling in trophoblasts in preeclampsia |
title_fullStr | NRP1 and MMP9 are dual targets of RNA‐binding protein QKI5 to alter VEGF‐R/ NRP1 signalling in trophoblasts in preeclampsia |
title_full_unstemmed | NRP1 and MMP9 are dual targets of RNA‐binding protein QKI5 to alter VEGF‐R/ NRP1 signalling in trophoblasts in preeclampsia |
title_short | NRP1 and MMP9 are dual targets of RNA‐binding protein QKI5 to alter VEGF‐R/ NRP1 signalling in trophoblasts in preeclampsia |
title_sort | nrp1 and mmp9 are dual targets of rna‐binding protein qki5 to alter vegf‐r/ nrp1 signalling in trophoblasts in preeclampsia |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184681/ https://www.ncbi.nlm.nih.gov/pubmed/33942999 http://dx.doi.org/10.1111/jcmm.16580 |
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