Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, 40, Daxue Road, Zhengzhou, 450052, Henan, China.
Cell Commun Signal. 2023 Jul 21;21(1):179. doi: 10.1186/s12964-023-01201-5.
The production of human chorionic gonadotropin (hCG) by the placental trophoblast cells is essential for maintaining a normal pregnancy. Aberrant hCG levels are associated with reproductive disorders. The protein of hCG is a dimer consisting of an α subunit and a β subunit. The β subunit is encoded by the CGB gene and is unique to hCG. Growth differentiation factor-11 (GDF-11), a member of the transforming growth factor-β (TGF-β) superfamily, is expressed in the human placenta and can stimulate trophoblast cell invasion. However, whether the expression of CGB and the production of hCG are regulated by GDF-11 remains undetermined.
Two human choriocarcinoma cell lines, BeWo and JEG-3, and primary cultures of human cytotrophoblast (CTB) cells were used as experimental models. The effects of GDF-11 on CGB expression and hCG production, as well as the underlying mechanisms, were explored by a series of in vitro experiments.
Our results show that treatment of GDF-11 downregulates the expression of CGB and the production of hCG in both BeWo and JEG-3 cells as well as in primary CTB cells. Using a pharmacological inhibitor and siRNA-mediated approach, we reveal that both ALK4 and ALK5 are required for the GDF-11-induced downregulation of CGB expression. In addition, treatment of GDF-11 activates SMAD2/3 but not SMAD1/5/8 signaling pathways. Moreover, both SMAD2 and SMAD3 are involved in the GDF-11-downregulated CGB expression. ELISA results show that the GDF-11-suppressed hCG production requires the ALK4/5-mediated activation of SMAD2/3 signaling pathways.
This study not only discovers the biological function of GDF-11 in the human placenta but also provides important insights into the regulation of the expression of hCG. Video Abstract.
胎盘滋养层细胞产生人绒毛膜促性腺激素（hCG）对于维持正常妊娠至关重要。异常的 hCG 水平与生殖障碍有关。hCG 蛋白是由一个α亚基和一个β亚基组成的二聚体。β亚基由 CGB 基因编码，是 hCG 所特有的。生长分化因子-11（GDF-11）是转化生长因子-β（TGF-β）超家族的成员，在人胎盘表达，可以刺激滋养层细胞侵袭。然而，CGB 的表达和 hCG 的产生是否受 GDF-11 调节尚不清楚。
使用人绒癌细胞系 BeWo 和 JEG-3 以及人绒毛细胞滋养层（CTB）细胞的原代培养作为实验模型，通过一系列体外实验探讨了 GDF-11 对 CGB 表达和 hCG 产生的影响及其潜在机制。
我们的结果表明，GDF-11 处理下调了 BeWo 和 JEG-3 细胞以及原代 CTB 细胞中 CGB 的表达和 hCG 的产生。使用药理学抑制剂和 siRNA 介导的方法，我们揭示了 ALK4 和 ALK5 都参与了 GDF-11 诱导的 CGB 表达下调。此外，GDF-11 处理激活了 SMAD2/3，但不激活 SMAD1/5/8 信号通路。此外，SMAD2 和 SMAD3 都参与了 GDF-11 下调的 CGB 表达。ELISA 结果表明，GDF-11 抑制的 hCG 产生需要 ALK4/5 介导的 SMAD2/3 信号通路的激活。
本研究不仅发现了 GDF-11 在人胎盘中的生物学功能，还为 hCG 的表达调控提供了重要见解。
