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

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. 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. 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. 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. © 2022. The Author(s).

Citation

Lanlan Fang, Yang Yan, Yibo Gao, Ze Wu, Zhen Wang, Sizhu Yang, Jung-Chien Cheng, Ying-Pu Sun. TGF-β1 inhibits human trophoblast cell invasion by upregulating kisspeptin expression through ERK1/2 but not SMAD signaling pathway. Reproductive biology and endocrinology : RB&E. 2022 Jan 31;20(1):22

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PMID: 35101033

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