MicroRNA-376c Impairs Transforming Growth Factor-β and Nodal Signaling to Promote Trophoblast Cell Proliferation and Invasion

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 61; no. 4; pp. 864 - 872
• Main Authors: Fu, Guodong, Ye, Gang, Nadeem, Lubna, Ji, Lei, Manchanda, Tanita, Wang, Yongqing, Zhao, Yangyu, Qiao, Jie, Wang, Yan-Ling, Lye, Stephen, Yang, Burton B., Peng, Chun
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01.04.2013; Lippincott Williams & Wilkins
• Subjects: Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cell Proliferation; Diseases of mother, fetus and pregnancy; Female; Gene Expression Regulation; Gynecology. Andrology. Obstetrics; Humans; Medical sciences; MicroRNAs - genetics; MicroRNAs - metabolism; Nodal Protein - biosynthesis; Nodal Protein - genetics; Placenta - cytology; Placenta - metabolism; Pre-Eclampsia - genetics; Pre-Eclampsia - metabolism; Pregnancy; Pregnancy. Fetus. Placenta; RNA - genetics; Signal Transduction - genetics; Transforming Growth Factor beta - biosynthesis; Transforming Growth Factor beta - genetics; Trophoblasts - cytology; Trophoblasts - metabolism; Hypertension; Cell proliferation; Pregnancy disorders; Lymph node; Fetal membrane; Transforming growth factor β; miR-376c; Cardiovascular disease; ALK7; Tumorous infiltration; Malignant tumor; Metastasis; ALK5; Pregnancy toxemia; Invasion; Pregnancy; Nodal; Placenta; Preeclampsia; TGF-β; Circulatory system; Cancer
• ISSN: 0194-911X; 1524-4563; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.111.203489

Preeclampsia is a major disorder of pregnancy and a leading cause of maternal and perinatal morbidity and mortality. MicroRNAs are small noncoding RNAs that regulate gene expression posttranscriptionally. In this study, we examined the expression of miR-376c and found that miR-376c levels were downregulated in both placental and plasma samples collected from preeclamptic patients, when compared with the normal pregnant women at the same gestational stage. Overexpression of miR-376c induced trophoblast cell proliferation, migration, and invasion in HTR8/SVneo cells and promoted placental explant outgrowth. In contrast, inhibition of endogenous miR-376c resulted in a decrease in trophoblast cell invasion and placental explant outgrowth. We identified activin receptor-like kinase 5 (ALK5), a type I receptor for transforming growth factor-β, and ALK7, a type I receptor for Nodal, as targets of miR-376c. Overexpression of miR-376c repressed transforming growth factor-β and Nodal functions, whereas overexpression of ALK5 and ALK7 reversed the effects of miR-376c. These results demonstrate that miR-376c inhibits both ALK5 and ALK7 expression to impair transforming growth factor-β/Nodal signaling, leading to increases in cell proliferation and invasion. An unbalanced Nodal/transforming growth factor-β and miR-376c expression may lead to the development of preeclampsia.