2. Academic Validation
  3. miR21 modulates the Hippo signaling pathway via interference with PP2A Bβ to inhibit trophoblast invasion and cause preeclampsia

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

  • Mol Ther Nucleic Acids. 2022 Sep 20:30:143-161. doi: 10.1016/j.omtn.2022.09.006.
Mingyu Hu 1,  Yangxi Zheng 1 2,  Jiujiang Liao 1 3,  Li Wen 1,  Juan Cheng 1,  Jiayu Huang 4,  Biao Huang 1,  Li Lin 1,  Yao Long 1,  Yue Wu 1,  Xuan Ye 1,  Yong Fu 1,  Hongbo Qi 1 3,  Philip N Baker 5,  Chao Tong 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
  • 2 Department of Stem Cell Transplantation and Cell Therapy, MD Anderson Cancer Center, Houston, TX 77054, USA.
  • 3 Department of Obstetrics, Chongqing Women and Children's Hospital of Chongqing Medical University, 401147, China.
  • 4 Reproductive Medicine Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
  • 5 College of Life Sciences, University of Leicester, Leicester LE1 7RH, UK.
PMID: 36250210 DOI: 10.1016/j.omtn.2022.09.006
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.

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