Department of Fetal Medicine and Prenatal Diagnosis, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China; Obstetrics and Gynecology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
Department of Fetal Medicine and Prenatal Diagnosis, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China; Obstetrics and Gynecology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
Placenta. 2023 Nov;143:34-44. doi: 10.1016/j.placenta.2023.09.009. Epub 2023 Sep 30.
Fetal growth restriction (FGR) is one of the most common complications of an abnormal pregnancy. Placental dysplasia has been established as a significant contributing factor to FGR. Zinc finger protein 554 (ZNF554) is a member of the Krüppel-associated box domain zinc finger protein subfamily, primarily expressed in the placenta and essential for maintaining normal pregnancy outcomes. However, its precise role in FGR remains uncertain. In this study, we confirmed that ZNF554 was low expressed in the placenta of the FGR pregnancy. To further elucidate the impact of ZNF554 on trophoblasts, we conducted experiments using siRNA and overexpression plasmids on HTR8/SVneo and JEG3 cells. Our findings revealed that silencing ZNF554 increased apoptosis and inhibited migration and invasion, while overexpression reduced apoptosis and promoted migration and invasion. Notably, ZNF554 knockdown decreased cellular antioxidant capacity and elevated the production of reactive oxygen species (ROS). Conversely, ZNF554 activated the nuclear factor E2-related factor 2 (NRF2) signaling pathway, exerting its antioxidant effects. Additionally, ZNF554 knockdown promoted cellular autophagy by suppressing P62 and enhancing LC3-II/LC3-I expression. Importantly, the antioxidant N-acetylcysteine (NAC) partially mitigated the impact of ZNF554 knockdown on mitochondrial ROS in trophoblast cells and subsequent effects on cellular autophagy and apoptosis. In conclusion, our results suggest that ZNF554 plays a pivotal role in modulating trophoblast cell invasion and may serve as a prognostic marker and potential therapeutic target for FGR.
胎儿生长受限（FGR）是异常妊娠最常见的并发症之一。胎盘发育不良已被确定为 FGR 的一个重要致病因素。锌指蛋白 554（ZNF554）是 Krüppel 相关盒结构域锌指蛋白亚家族的成员，主要在胎盘表达，对维持正常妊娠结局至关重要。然而，其在 FGR 中的确切作用尚不清楚。在本研究中，我们证实 ZNF554 在 FGR 妊娠的胎盘中低表达。为了进一步阐明 ZNF554 对滋养层的影响，我们使用 siRNA 和过表达质粒在 HTR8/SVneo 和 JEG3 细胞中进行了实验。我们的研究结果表明，沉默 ZNF554 增加了滋养层细胞的凋亡并抑制了其迁移和侵袭，而过表达则降低了凋亡并促进了迁移和侵袭。值得注意的是，ZNF554 敲低降低了细胞抗氧化能力并增加了活性氧（ROS）的产生。相反，ZNF554 激活了核因子 E2 相关因子 2（NRF2）信号通路，发挥其抗氧化作用。此外，ZNF554 敲低通过抑制 P62 和增强 LC3-II/LC3-I 的表达促进了细胞自噬。重要的是，抗氧化剂 N-乙酰半胱氨酸（NAC）部分减轻了 ZNF554 敲低对滋养层细胞线粒体 ROS 的影响以及随后对细胞自噬和凋亡的影响。总之，我们的研究结果表明，ZNF554 在调节滋养层细胞侵袭中起关键作用，可能作为 FGR 的预后标志物和潜在治疗靶点。
