miR21 modulates the Hippo signaling pathway via interference with PP2A Bf3 to inhibit trophoblast invasion and cause preeclampsia

作者全名："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.; Tong, Chao"

作者地址："[Hu, Mingyu; Zheng, Yangxi; Liao, Jiujiang; Wen, Li; Cheng, Juan; Huang, Biao; Lin, Li; Long, Yao; Wu, Yue; Ye, Xuan; Fu, Yong; Qi, Hongbo; Tong, Chao] Chongqing Med Univ, State Key Lab Maternal & Fetal Med Chongqing Munic, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Zheng, Yangxi] MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cell Therapy, Houston, TX 77054 USA; [Liao, Jiujiang; Qi, Hongbo] Chongqing Med Univ, Dept Obstet, Chongqing Women & Childrens Hosp, Chongqing 401147, Peoples R China; [Huang, Jiayu] Chongqing Med Univ, Reprod Med Ctr, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Baker, Philip N.] Univ Leicester, Coll Life Sci, Leicester LE1 7RH, Leicestershire, England; [Qi, Hongbo; Tong, Chao] Chongqing Med Univ, State Key Lab Maternal & Fetal Med Chongqing Munic, Affiliated Hosp 1, 1 Youyi Rd, Chongqing 400016, Peoples R China"

通信作者："Qi, HB; Tong, C (通讯作者)，Chongqing Med Univ, State Key Lab Maternal & Fetal Med Chongqing Munic, Affiliated Hosp 1, 1 Youyi Rd, Chongqing 400016, Peoples R China."

来源：MOLECULAR THERAPY-NUCLEIC ACIDS

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:000870031800008

JCR分区：Q1

影响因子：8.8

年份：2022

卷号：30

期号：　

开始页：143

结束页：161

文献类型：Article

关键词：　

摘要："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 tropho-blast invasion and migration, in preeclamptic placentae. Whole-genome RNA sequencing revealed that PPP2R2B, which encodes PP2A BO, and the Hippo pathway are down-stream targets of miR21. The effects of miR21 on trophoblast mobility were abolished in LATS1T1079A/S909A and YAP-5SA mutants. Moreover, we found that PP2A BO dephosphory-lates 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 upre-gulation 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 BO/Hippo axis, which is one of the causes of PE."

基金机构："National Natural Science Foundation of China [81871189, 82071675, 82001580, U21A20346, 82101711, 82171662]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (81871189, 82071675, 82001580, U21A20346, 82101711, and 82171662). We thank CapitalBio Tech and Novogene for assisting 10 Chi single-cell and whole-genome RNA sequencing, respectively."