TGF-β1 inhibits human trophoblast cell invasion by upregulating kisspeptin expression through ERK1/2 but not SMAD signaling pathway

Abstract

Background Tightly regulation of extravillous cytotrophoblast (EVT) cell invasion is critical for the placentation and establishment of a successful pregnancy. Insufficient EVT cell invasion leads to the development of preeclampsia (PE) which is a leading cause of maternal and perinatal mortality and morbidity. Transforming growth factor-beta1 (TGF-β1) and kisspeptin are expressed in the human placenta and have been shown to inhibit EVT cell invasion. Kisspeptin is a downstream target of TGF-β1 in human breast cancer cells. However, whether kisspeptin is regulated by TGF-β1 and mediates TGF-β1-suppressed human EVT cell invasion remains unclear. Methods The effect of TGF-β1 on kisspeptin expression and the underlying mechanisms were explored by a series of in vitro experiments in a human EVT cell line, HTR-8/SVneo, and primary cultures of human EVT cells. Serum levels of TGF-β1 and kisspeptin in patients with or without PE were measured by ELISA. Results TGF-β1 upregulates kisspeptin expression in HTR-8/SVneo cells and primary cultures of human EVT cells. Using pharmacological inhibitor and siRNA, we demonstrate that the stimulatory effect of TGF-β1 on kisspeptin expression is mediated via the ALK5 receptor. Treatment with TGF-β1 activates SMAD2/3 canonical pathways as well as ERK1/2 and PI3K/AKT non-canonical pathways. However, only inhibition of ERK1/2 activation attenuates the stimulatory effect of TGF-β1 on kisspeptin expression. In addition, siRNA-mediated knockdown of kisspeptin attenuated TGF-β1-suppressed EVT cell invasion. Moreover, we report that serum levels of TGF-β1 and kisspeptin are significantly upregulated in patients with PE. Conclusions By illustrating the potential physiological role of TGF-β1 in the regulation of kisspeptin expression, our results may serve to improve current strategies used to treat placental diseases.

Kisspeptin treatment improves fetal-placental development and blocks placental oxidative damage caused by maternal hypothyroidism in an experimental rat model

“…Therefore, failures in the kisspeptin/Kiss1R signaling system result in hypogonadotropic hypogonadism (3,4). In addition to its hypothalamic action, however, the kisspeptin/Kiss1R system is expressed in a variety of tissues, including the placenta (5,6), although studies on the action of kisspeptin on the placenta are still scarce (7)(8)(9).…”

“…This suggests that the placenta is one of the main sources of systemic kisspeptin. Studies have shown that kisspeptin influences the adhesion and implantation of blastocysts and the decidualization and migration of trophoblasts, and regulates the immunological profile and uterine natural killer cells (uNKs) (5,(7)(8)(9)(11)(12)(13)(14)(15)(16)(17), suggesting that faults in its expression in the maternal-fetal interface may be involved in placental disorders (12,18).…”

The Role of Kisspeptin in the Pathogenesis of Pregnancy Complications: A Narrative Review

“…It is suggested that binding KISS-1R with the ligand in the placenta may decrease their expression in syncytiotrophoblast, as in thyrotropin-releasing hormone [ 47 ]. The latest experimental research indicates that transforming growth factor β-1 (TGF β-1) upregulates kisspeptin expression in human extravillous cytotrophoblast cells by inhibiting the ERK1/2 signaling pathway and, in this way, it leads to decreased trophoblast cell invasion [ 48 ]. The process of kisspeptin isoforms formation, as well as its various signaling pathways, are presented in Figure 1 .…”

“…The latest in vitro experimental study has shown that TGF-β, which is also expressed in the human placenta and is responsible for the regulation of cellular processes, seems to inhibit human trophoblast cells’ invasion by upregulating kisspeptin expression through the ERK1/2 signaling pathway [ 48 ]. Furthermore, numerous studies have revealed that kisspeptin may restrain the trophoblast growth by activating apoptosis in a dose-depended manner, together with pro-inflammatory cytokines, including tumor necrosis factor α (TNF-α) [ 96 , 97 , 98 ].…”

“…Numerous clinical studies have revealed that preeclamptic women presented elevated plasma [ 11 ] or serum [ 48 , 111 ] kisspeptin levels compared with healthy individuals. The research conducted by Abbara et al has shown that plasma kisspeptin level in pregnancies complicated by hypertensive disorders was significantly increased than in healthy ones (OR of hypertensive pregnancies was increased by 30% (95% CI, 16–47%; p < 0.0001) for every 1 nmol/L increase in kisspeptin concentration) [ 11 ].…”