title: MicroRNA-376c impairs transforming growth factor-β and nodal signaling to promote trophoblast cell proliferation and invasion.
abstract: 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.
authors: Department of Biology, York University, Toronto, Ontario, Canada.
authors: Guodong
authors: G
authors: Fu
authors: Gang
authors: G
authors: Ye
authors: Lubna
authors: L
authors: Nadeem
authors: Lei
authors: L
authors: Ji
authors: Tanita
authors: T
authors: Manchanda
authors: Yongqing
authors: Y
authors: Wang
authors: Yangyu
authors: Y
authors: Zhao
authors: Jie
authors: J
authors: Qiao
authors: Yan-Ling
authors: YL
authors: Wang
authors: Stephen
authors: S
authors: Lye
authors: Burton B
authors: BB
authors: Yang
authors: Chun
authors: C
authors: Peng
mesh_terms: D049109:Cell Proliferation; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D055457:Nodal Protein / Q000096:biosynthesis / Q000235:genetics*; D010920:Placenta / Q000166:cytology / Q000378:metabolism; D011225:Pre-Eclampsia / Q000235:genetics* / Q000378:metabolism; D011247:Pregnancy; D012313:RNA / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics*; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D055457:Nodal Protein; D016212:Transforming Growth Factor beta; D012313:RNA