miR21 modulates the Hippo signaling pathway via interference with PP2A Bβ to inhibit trophoblast invasion and cause preeclampsia

Hu, Mingyu, Zheng, Yangxi, Liao, Jiujiang, Wen, Li, Cheng, Juan, Huang, Jiayu, Huang, Biao, Lin, Li, Long, Yao, Wu, Yue, Ye, Xuan, Fu, Yong, Qi, Hongbo, Baker, Philip N. and Tong, Chao (2022) miR21 modulates the Hippo signaling pathway via interference with PP2A Bβ to inhibit trophoblast invasion and cause preeclampsia. Molecular Therapy Nucleic Acids, 30. pp. 143-161. ISSN 2162-2531

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Abstract

Preeclampsia (PE) is a pregnancy-specific disorder attributed to deficient extravillous trophoblast (EVT) invasion into the uterus, but the mechanism of EVT invasion remains unclear. In this study, we found significantly elevated expression of microRNA 21 (miR21), which negatively regulates trophoblast invasion and migration, in preeclamptic placentae. Whole-genome RNA sequencing revealed that PPP2R2B, which encodes PP2A Bβ, and the Hippo pathway are downstream targets of miR21. The effects of miR21 on trophoblast mobility were abolished in LATS1T1079A/S909A and YAP-5SA mutants. Moreover, we found that PP2A Bβ dephosphorylates LATS1 via direct protein-protein interactions and thus modulates the phosphorylation and subcellular distribution of YAP. PPP2R2B overexpression ameliorated the miR21-induced LATS1-YAP phosphorylation and cytoplasmic sequestration of YAP, which resulted in the rescue of compromised trophoblast invasion and migration. The upregulation of placental miR21 abundance by placenta-specific nanoparticles loaded with agomir-miR21 during placentation interfered with PPP2R2B and activated the Hippo pathway in the placenta, leading to a PE-like phenotype. Thus, aberrant elevation of miR21 impairs EVT mobility by modulating the PP2A Bβ/Hippo axis, which is one of the causes of PE.

Item Type:	Article
Additional Information:	Data and code availability: The data and materials described in the manuscript will be available upon reasonable request made to the corresponding authors (delivery charges and agreement of usage may apply). Funding information: This study was funded by the National Key R&D Program of China (2022YFC2702400), the National Natural Science Foundation of China (81871189, 82071675, 82001580, U21A20346, 82101711, and 82171662).
Uncontrolled Keywords:	hippo,invasion,mir21,mt: non-coding rnas,pp2a bβ,preeclampsia,trophoblast,molecular medicine,drug discovery ,/dk/atira/pure/subjectarea/asjc/1300/1313
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Related URLs:	http://www.scopus.com/inward/record.url?...
Depositing User:	LivePure Connector
Date Deposited:	08 May 2025 08:34
Last Modified:	08 May 2025 08:34
URI:	https://ueaeprints.uea.ac.uk/id/eprint/99209
DOI:	10.1016/j.omtn.2022.09.006

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