Yuan Dong, Yang Zhu, Chen Yiyu, Li Siyuan, Tan Benxu, Yu Qiubo
Department of Gynecology, Chongqing Medical University Affiliated Second Hospital, Chongqing, China.
Molecular Medical Laboratory, Institute of Life Sciences, Chongqing Medical University, Chongqing, China.
Cell Biol Int. 2021 Mar;45(3):599-611. doi: 10.1002/cbin.11501. Epub 2021 Jan 13.
Placental hypoxia has been implicated in pregnancy pathologies such as pre-eclampsia and intrauterine growth restriction. However, the underlying mechanism by which the trophoblasts respond to hypoxia remains unclear. Speckle-type POZ protein (SPOP), an E3 ubiquitin ligase adapter, was previously reported to play important roles in various physiological and pathological processes. This study aims to investigate the expression and biological functions of SPOP after exposure to cobalt chloride (CoCl )-mimicked hypoxia conditions using human trophoblast-derived choriocarcinoma cell lines and extravillous cytotrophoblast. These data showed that SPOP protein was directly induced by CoCl -mimicked hypoxia and regulated by HIF-1α at the posttranscription level. CoCl treatment could dramatically influence the localization of SPOP in trophoblasts, especially the accumulation of SPOP into the nucleus. In addition, both CoCl -mimicked hypoxia and induction of endogenous SPOP expression by lentivirus transfection attenuated the migration and invasion abilities of trophoblasts. Furthermore, we demonstrated that SPOP was involved in CoCl -induced the inhibition of the PI3K/AKT/GSK3β pathway in placental trophoblasts. Taken together, these data indicate that accumulation of HIF-1α augments the expression of SPOP in trophoblasts, which impairs trophoblastic mobility by targeting the PI3K/AKT/GSK3β pathway. This potentially leads to insufficient uterine spiral artery remodeling and suboptimal placental perfusion, and thus the development of pregnancy-related complication.
胎盘缺氧与子痫前期和胎儿宫内生长受限等妊娠病理情况有关。然而，滋养层细胞对缺氧作出反应的潜在机制仍不清楚。斑点型POZ蛋白（SPOP）是一种E3泛素连接酶衔接蛋白，此前报道其在各种生理和病理过程中发挥重要作用。本研究旨在使用人滋养层来源的绒毛膜癌细胞系和绒毛外细胞滋养层，研究在氯化钴（CoCl₂）模拟的缺氧条件下SPOP的表达及生物学功能。这些数据表明，SPOP蛋白由CoCl₂模拟的缺氧直接诱导，并在转录后水平受缺氧诱导因子-1α（HIF-1α）调控。CoCl₂处理可显著影响SPOP在滋养层细胞中的定位，尤其是SPOP在细胞核中的积累。此外，CoCl₂模拟的缺氧和通过慢病毒转染诱导内源性SPOP表达均减弱了滋养层细胞的迁移和侵袭能力。此外，我们证明SPOP参与了CoCl₂诱导的胎盘滋养层细胞中PI3K/AKT/GSK3β信号通路的抑制。综上所述，这些数据表明HIF-１α的积累增强了滋养层细胞中SPOP的表达，后者通过靶向PI3K/AKT/GSK3β信号通路损害滋养层细胞的迁移能力。这可能导致子宫螺旋动脉重塑不足和胎盘灌注欠佳，进而引发妊娠相关并发症。
