Chen Jie, Zheng Youhong, Hang Lilin, Wang Huiyan
Department of Obstetrics & Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
Department of Obstetrics & Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
Taiwan J Obstet Gynecol. 2025 Jul;64(4):662-670. doi: 10.1016/j.tjog.2025.01.006.
Preeclampsia (PE) is an idiopathic and life-threatening pregnancy-related disease. Alterations to DNA methylation in imprinted genes may play a crucial role in the dysfunction of trophoblast cells and PE.
Herein, we sought to elucidate the characteristics of PHLDA2 in placental trophoblasts and its underlying mechanisms in pregnant women with PE. Between January 2019 and December 2021, the clinical data and placental tissue samples from 15 PE cases and 15 control women who underwent obstetric examination were collected. Immunohistochemistry, qRT-PCR, WB and pyrosequencing were used to detect and compare the expression and methylation status of imprinted gene PHLDA2 in placental tissues of the two groups.
The expression levels of PHLDA2 mRNA and protein were significantly higher in the placental tissue of PE patients than those of healthy controls during the third trimester (P = 0.001). Additionally, PHLDA2 expression levels were evaluated in four trophoblast cell lines, with the JEG-3 line showing the lowest expression of PHLDA2. Notably, the JEG-3 line demonstrated a significantly faster rate of proliferation compared to the other three cell lines. When the PHLDA2 was overexpressed in JEG-3 cells, the proliferative proteins were significantly reduced, while the expression levels of apoptosis-related proteins p27 and cleaved-caspase3 were significantly increased. In addition, pyrosequencing showed that the methylation levels of the PHLDA2 promoter region were significantly lower in PE placentas than in controls.
The hypomethylation status of the PHLDA2 promoter is associated with its altered expression in PE placentas, suggesting a potential role in the condition's pathogenesis.
子痫前期（PE）是一种与妊娠相关的特发性且危及生命的疾病。印迹基因中DNA甲基化的改变可能在滋养层细胞功能障碍和PE中起关键作用。
在此，我们试图阐明胎盘滋养层细胞中PHLDA2的特征及其在PE孕妇中的潜在机制。在2019年1月至2021年12月期间，收集了15例PE病例和15例接受产科检查的对照女性的临床资料和胎盘组织样本。采用免疫组织化学、qRT-PCR、WB和焦磷酸测序检测并比较两组胎盘组织中印迹基因PHLDA2的表达和甲基化状态。
在妊娠晚期，PE患者胎盘组织中PHLDA2 mRNA和蛋白的表达水平显著高于健康对照组（P = 0.001）。此外，在四种滋养层细胞系中评估了PHLDA2的表达水平，其中JEG-3细胞系中PHLDA2的表达最低。值得注意的是，与其他三种细胞系相比，JEG-3细胞系的增殖速度明显更快。当在JEG-3细胞中过表达PHLDA2时，增殖蛋白显著减少，而凋亡相关蛋白p27和裂解的caspase3的表达水平显著增加。此外，焦磷酸测序显示，PE胎盘组织中PHLDA2启动子区域的甲基化水平显著低于对照组。
PHLDA2启动子的低甲基化状态与其在PE胎盘中表达的改变有关，提示其在该疾病发病机制中可能发挥作用。
