miR21 Modulates the Hippo Signaling Pathway via Interference With PP2A Bβ to Inhibit Trophoblast Invasion and Cause Preeclampsia

Authors

Mingyu Hu
Yangxi Zheng
Jiujiang Liao
Li Wen
Juan Cheng
Jiayu Huang
Biao Huang
Li Lin
Yao Long
Yue Wu
Xuan Ye
Yong Fu
Hongbo Qi
Philip N Baker
Chao Tong

Publication Date

12-13-2022

Journal

Molecular Therapy Nucleic Acids

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.

Keywords

MT: Non-coding RNAs, PP2A Bβ, hippo, invasion, miR21, preeclampsia, trophoblast, MT: Non-coding RNAs, preeclampsia, miR21, PP2A Bβ, hippo, trophoblast, invasion

DOI

10.1016/j.omtn.2022.09.006

PMID

36250210

PMCID

PMC9547189

PubMedCentral® Posted Date

9-20-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes