Zhang Jiashuo, Mei Lan, Zhang Yanping, Wei Xiaohong, Liu Min, Yin Yangxue, Xu Qin, Liao Lingyun, Gao Linbo, Zhou Rong
Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
FASEB J. 2025 Jun 30;39(12):e70736. doi: 10.1096/fj.202500351R.
Abnormal spiral artery remodeling is the starting point of preeclampsia. Placental lncRNA-ATB levels are significantly reduced in patients with severe preeclampsia (sPE), and these reduced levels can inhibit the biological functions of HTR-8/SVneo trophoblasts. However, the mechanism by which lncRNA-ATB regulates the biological behavior of trophoblasts remains unclear. Here, we aimed to identify proteins that interact with lncRNA-ATB in trophoblasts and uncover the biological regulatory mechanism associated with this molecule. In this study, RNA-protein pull-down and RNA immunoprecipitation tests were used to identify lncRNA-ATB downstream factors. Poly(A)-binding protein cytoplasmic 1 (PABPC1) was a target protein of lncRNA-ATB, and its expression was positively regulated by lncRNA-ATB in trophoblasts. Reduced PABPC1 expression inhibited proliferation, migration, invasion, and tube formation, and enhanced apoptosis in trophoblast cells. In sPE-affected placentas, PABPC1 expression was reduced, which may have mediated the effect of lncRNA-ATB on MDM2. Moreover, MDM2 expression was inhibited after lncRNA-ATB or PABPC1 knockdown in trophoblasts, and reduced MDM2 expression suppressed trophoblast biological functions. Further, the interaction between PABPC1 and MDM2 was suggested to be mediated by p53, and p53 expression was negatively regulated by PABPC1. In summary, PABPC1 mediates the effects of lncRNA-ATB on trophoblast biological functions via the p53/MDM2 pathway. Our findings provide a new perspective on the role of lncRNA-ATB in sPE pathogenesis.
异常的螺旋动脉重塑是子痫前期的起始点。重度子痫前期（sPE）患者胎盘lncRNA-ATB水平显著降低，而这些降低的水平可抑制HTR-8/SVneo滋养层细胞的生物学功能。然而，lncRNA-ATB调节滋养层细胞生物学行为的机制仍不清楚。在此，我们旨在鉴定与滋养层细胞中lncRNA-ATB相互作用的蛋白质，并揭示与该分子相关的生物学调节机制。在本研究中，采用RNA-蛋白质下拉和RNA免疫沉淀试验来鉴定lncRNA-ATB的下游因子。多聚腺苷酸结合蛋白细胞质1（PABPC1）是lncRNA-ATB的靶蛋白，其表达在滋养层细胞中受到lncRNA-ATB的正向调节。PABPC1表达降低会抑制滋养层细胞的增殖、迁移、侵袭和管形成，并增强其凋亡。在受sPE影响的胎盘中，PABPC1表达降低，这可能介导了lncRNA-ATB对MDM2的影响。此外，在滋养层细胞中敲低lncRNA-ATB或PABPC1后，MDM2表达受到抑制，而MDM2表达降低会抑制滋养层细胞的生物学功能。此外，提示PABPC1与MDM2之间的相互作用由p53介导，且PABPC1对p53表达起负向调节作用。总之，PABPC1通过p53/MDM2途径介导lncRNA-ATB对滋养层细胞生物学功能的影响。我们的研究结果为lncRNA-ATB在sPE发病机制中的作用提供了新的视角。
