Smurf2 participates in human trophoblast cell invasion by inhibiting TGF-beta type I receptor.
Successful embryo implantation depends on the ability of the trophoblast cells to invade the endometrium and the receptivity of the endometrium. Unlike tumor invasion, trophoblast invasion is spatio-temporaly restricted. Transforming growth factor (TGF)-beta is a key inhibitory factor in the invasion of early trophoblast cells. Smad ubiquitination regulatory factor 2 (Smurf2), a HECT type E3 ubiquitin ligase, is an important regulator of the TGF-beta signaling pathway, targeting TGF-beta receptors and various Smads for proteasome-mediated degradation. In this context, we wished to determine whether Smurf2 has a physiological role during embryo implantation, especially in trophoblast invasion. We examined the spatio-temporal expression of Smurf2 in human placental villi and the function of Smurf2 in trophoblast cell migration and invasion in a model system involving a human extravillous trophoblast cell line, HTR-8/SVneo. Results from RT-PCR and immunohistochemical studies showed that expression of Smurf2 in placental villi was the highest during the first trimester and decreased as the pregnancy progressed. Overexpression of Smurf2 in HTR-8/SVneo cells reduced TGF-beta type I receptor levels, and enhanced cell migration and invasion. Conversely, RNA interference-mediated downregulation of Smurf2 resulted in a significant increase in TGF-beta type I receptor protein levels. However, the levels of Smad2, another potential target of Smurf2, remained unchanged. In conclusion, the present study suggests that Smurf2 promotes trophoblast cell migration and invasion, and this function may involve downregulation of TGF-beta type I receptor.
Yang
Qing
Q
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Chen
Sheng-Ping
SP
Zhang
Xiao-Ping
XP
Wang
Hongmei
H
Zhu
Cheng
C
Lin
Hai-Yan
HY
D002460:Cell Line; D002465:Cell Movement; D002824:Chorionic Villi / Q000378:metabolism; D015536:Down-Regulation; D010064:Embryo Implantation; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D011247:Pregnancy; D011264:Pregnancy Trimesters; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D051899:Smad2 Protein / Q000096:biosynthesis; D014327:Trophoblasts / Q000166:cytology / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000502:physiology*
D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C498342:SMURF1 protein, human; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I