Abstract
Trophoblast invasion ability is an important factor in early implantation and placental development. Recently, pituitary tumor transforming gene 1 (PTTG1) was shown to be involved in invasion and proliferation of cancer. However, the role of PTTG1 in trophoblast invasion remains unknown. Thus, in this study we analyzed PTTG1 expression in trophoblasts and its effect on trophoblast invasion activity and determined the mechanism through which PTTG1 regulates trophoblast invasion. Trophoblast proliferation and invasion abilities, regardless of PTTG1 expression, were analyzed by quantitative real-time polymerase chain reaction, fluorescence-activated cell sorting analysis, invasion assay, western blot, and zymography after treatment with small interfering RNA against PTTG1 (siPTTG1). Additionally, integrin/Rho-family signaling in trophoblasts by PTTG1 alteration was analyzed. Furthermore, the effect of PTTG1 on trophoblast invasion was evaluated by microRNA (miRNA) mimic and inhibitor treatment. Trophoblast invasion was significantly reduced through decreased matrix metalloproteinase (MMP)-2 and MMP-9 expression when PTTG1 expression was inhibited by siPTTG1 (p < 0.05). Furthermore, knockdown of PTTG1 increased expression of integrin alpha 4 (ITGA4), ITGA5, and integrin beta 1 (ITGB1); otherwise, RhoA expression was significantly decreased (p < 0.05). Treatment of miRNA-186-5p mimic and inhibitor controlled trophoblast invasion ability by altering PTTG1 and MMP expression. PTTG1 can control trophoblast invasion ability via regulation of MMP expression through integrin/Rho-family signaling. In addition, PTTG1 expression and its function were regulated by miRNA-186-5p. These results help in understanding the mechanism through which PTTG1 regulates trophoblast invasion and thereby implantation and placental development.
Highlights
The placenta, which is a temporary organ during pregnancy, is formed from the outer layer of the blastocyst [1]
We demonstrated that hypoxia induced trophoblast invasion through dynamic alterations of integrin and matrix metalloproteinase (MMP) expression, especially through the down-regulation of integrin alpha 4 (ITGA4), which is observed in short-term hypoxia [7]
We investigated the effect of pituitary tumor transforming gene 1 (PTTG1) expression on the invasion of trophoblasts using small interfering RNA, and validated PTTG1 function using a miRNA target to PTTG1
Summary
The placenta, which is a temporary organ during pregnancy, is formed from the outer layer of the blastocyst (e.g., trophectoderm) [1]. The normal placenta plays a crucial role in fetal development by producing a variety of pregnancy-associated hormones and growth factors and supplying nutrients, and it acts as a maternal—fetal interface organ transporting waste products and gases [2]. Trophoblasts originating from the trophectoderm of the blastocyst are the major cells found in the placenta, and their main function is invasion of the maternal uterine wall during early pregnancy via transformation of spiral arteries and differentiation of cytotrophoblasts (CTBs) into syncytiotrophoblasts [3, 4]. Trophoblast invasion can be modulated by the expression of various genes, such as adhesion molecules, MMPs, small guanosine triphosphatases (GTPases), epithelial—mesenchymal transition (EMT)-related factors, and microRNAs (miRNAs) [8,9,10]
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