Role of kisspeptin/GPR54 in the first trimester trophoblast of women with a history of recurrent spontaneous abortion

Trophoblast migration and invasion during pregnancy are under strict physiological control, both temporally and spatially. The trophoblast’s ability to invade the endometrium is regulated by the dynamic interaction between invasion-related genes. Once this dynamic balance is broken, the trophoblast exhibits abnormal invasion ability, often resulting in recurrent spontaneous abortion (RSA). Kisspeptins, products of the KISS1 gene, were originally identified as metastasis suppressor peptides with the ability to bind G protein-coupled receptors (i.e., GPR54). The human placenta expresses both KISS1 and kisspeptin receptor (KISS1R) mRNA within the trophoblast compartment, where it is thought to inhibit physiological invasion. In order to explore the effects of KISS1 on the biological behavior of human trophoblasts and its association with RSA, we used immunohistochemistry to compare the expression of kisspeptin and GPR54 at the maternal-fetal interface in RSA cases and cases with normal pregnancy. Abortion-prone CBA/J×DBA/2 matings were established as a model for spontaneous abortion, while non-abortionprone CBA/J×BALB/c matings were used as a model for normal pregnancy. The expression of kisspeptin and GPR54 in mice placental tissues was compared by immunohistochemistry. Gene recombination and transfection technology were used to evaluate the effects of the KISS1 gene and kisspeptin on JAR cells in terms of proliferation, colony formation ability, and migration and invasion abilities. Kisspeptin/GPR54 revealed lower levels of expression at the maternal-fetal surface in RSA patients compared to controls (P<0.001). Similarly, the expression of kisspeptin/ GPR54 at the maternal-fetal interface of spontaneous-abortion mice (CBA/J×DBA/2) was remarkably lower than the group of mice that experienced normal pregnancy (CBA/J×BALB/c) (P<0.05). Data indicated that the KISS1 gene and kisspeptin play a significant role in the inhibition of trophoblast migration and invasion propensity in vitro without affecting cell growth or proliferation. Moreover, kisspeptin appeared to exert an effect in a dose-dependent manner. These data support the fact that the downregulation of kisspeptin/GPR54 may be related to RSA, and that the abnormal expression of KISS1 acts as an invasion-inhibitor gene. Consequently, KISS1 possesses the ability to interfere with normal homeostasis of trophoblast regulation, ultimately resulting in miscarriage.