Research Papers:

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

Lisa Zuckerwise, Jing Li, Lingeng Lu, Yi Men, Tingting Geng, Catalin S. Buhimschi, Irina A. Buhimschi, Radek Bukowski, Seth Guller, Michael Paidas and Yingqun Huang _

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Oncotarget. 2016; 7:38398-38407. https://doi.org/10.18632/oncotarget.9534

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Lisa Zuckerwise1,*, Jing Li1,2,*, Lingeng Lu3, Yi Men1,4, Tingting Geng1,5, Catalin S. Buhimschi6, Irina A. Buhimschi6,7,8, Radek Bukowski1, Seth Guller1, Michael Paidas1,9, Yingqun Huang1

1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA

2Deparment of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China

3Department of Chronic Diseases Epidemiology, Yale School of Public Health, Yale University School of Medicine, New Haven, CT, USA

4Department of Head and Neck Surgery, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, P.R. China

5Department of Endocrinology, School of Medicine, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, P.R. China

6Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, OH, USA

7Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA

8Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA

9Yale Women and Children's Center for Blood Disorders and Preeclampsia Advancement, Yale School of Medicine, New Haven, CT, USA

*These authors contributed equally to this work

Correspondence to:

Yingqun Huang, email: [email protected]

Keywords: fetal growth restriction, H19 long noncoding RNA, TβR3, trophoblast

Received: February 15, 2016     Accepted: May 08, 2016     Published: May 21, 2016


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.

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