Smurf2 Participates in Human Trophoblast Cell Invasion by Inhibiting TGF- Type I Receptor

Qing Yang ¹, Sheng-Ping Chen ¹, Xiao-Ping Zhang ¹, Hongmei Wang ¹, Cheng Zhu ¹ and Hai-Yan Lin ^1*

¹ State Key Laboratory of Reproductive Biology, Institute of Zoology (QY,X-PZ,HW,CZ,H-YL), and Graduate School (QY,X-PZ), Chinese Academy of Sciences, Beijing, China, and Department of Obstetrics and Gynecology, Xuanwu Hospital, Capital Medical University, Beijing, China (S-PC)

^* To whom correspondence should be addressed. E-mail: linhy{at}ioz.ac.cn.

Submitted on November 3, 2008
Accepted on 18 February 2009

	Abstract

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 spatiotemporily restricted. Transforming growth factor (TGF)- 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 TGF- signaling pathway, targeting TGF- 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 the expression decreased with the pregnancy processes. Over-expression of Smurf2 in HTR-8/SVneo cells reduced TGF- type I receptor levels, and enhanced cell migration and invasion. Conversely, RNAi-mediated down-regulation of Smurf2 resulted in significant increase of TGF- 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 down-regulation of TGF- type I receptor.

Key Words: Smurf2, invasion, migration, trophoblast, TGF- type I receptor

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