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Oncotarget. 2016 Jun 21;7(25):38398-38407. doi: 10.18632/oncotarget.9534.

H19 long noncoding RNA alters trophoblast cell migration and invasion by regulating TβR3 in placentae with fetal growth restriction.

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Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
Deparment of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China.
Department of Chronic Diseases Epidemiology, Yale School of Public Health, Yale University School of Medicine, New Haven, CT, USA.
Department of Head and Neck Surgery, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, P.R. China.
Department of Endocrinology, School of Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.
Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, OH, USA.
Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.
Yale Women and Children's Center for Blood Disorders and Preeclampsia Advancement, Yale School of Medicine, New Haven, CT, USA.


Fetal growth restriction (FGR) is a well-recognized risk factor for perinatal mortality and morbidity, as well as neurodevelopmental impairment and adulthood onset disorders. Here we report that the H19 long noncoding RNA (lncRNA) is significantly decreased in placentae from pregnancies with FGR. Downregulation of H19 leads to reduced migration and invasion of extravillous trophoblast (EVT) cells in vitro. This is consistent with reduced trophoblast invasion that has been observed in FGR. Genome-scale transcriptome profiling of EVT cells reveals significantly decreased expression of the type III TGF-β receptor (TβR3) following H19 knockdown. Decreased TβR3 expression is also seen in FGR placentae. TβR3 repression decreases EVT cell migration and invasion, owing to impaired TGF-β signaling through a non-canonical TGF-β signaling pathway. Further, we identify TβR3 as a novel regulatory target of microRNA let-7. We propose that dysregulation of this newly identified H19/TβR3-mediated regulatory pathway may contribute to the molecular mechanism of FGR. Our findings are the first to show a lncRNA-based mechanism of FGR, holding promise for the development of novel predictive, diagnostic, and therapeutic modalities for FGR.


H19 long noncoding RNA; TβR3; fetal growth restriction; trophoblast

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