Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, Tampa, Florida, USA.
Department of Obstetrics and Gynecology, Morsani College of Medicine, Tampa, Florida, USA.
FASEB J. 2019 Feb;33(2):2759-2769. doi: 10.1096/fj.201801163R. Epub 2018 Oct 11.
Preeclampsia (PE) is a common cause of maternal morbidity, characterized by impaired trophoblast invasion and spiral artery transformation resulting in progressive uteroplacental hypoxia. Given the primary role of LIN28A and LIN28B in modulating cell metabolism, differentiation, and invasion, we hypothesized that LIN28A and/or LIN28B regulates trophoblast differentiation and invasion, and that its dysregulation may contribute to PE. Here we show that LIN28B is expressed ∼1300-fold higher than LIN28A in human term placenta and is the predominant paralog expressed in primary human trophoblast cultures. The expression of LIN28B mRNA and protein levels are significantly reduced in gestational age-matched preeclamptic vs. normal placentas, whereas LIN28A expression is not different. First trimester human placental sections displayed stronger LIN28B immunoreactivity in extravillous (invasive) cytotrophoblasts and syncytial sprouts vs. villous trophoblasts. LIN28B overexpression increased HTR8 cell proliferation, migration, and invasion, whereas LIN28B knockdown in JEG3 cells reduced cell proliferation. Moreover, LIN28B knockdown in JEG3 cells suppressed syncytin 1 (SYN-1), apelin receptor early endogenous ligand (ELABELA), and the chromosome 19 microRNA cluster, and increased mRNA expression of ITGβ4 and TNF-α. Incubation of BeWo and JEG3 cells under hypoxia significantly decreased expression of LIN28B and LIN28A, SYN-1, and ELABELA, whereas TNF-α is increased. These results provide the first evidence that LIN28B is the predominant paralog in human placenta and that decreased LIN28B may play a role in PE by reducing trophoblast invasion and syncytialization, and by promoting inflammation.-Canfield, J., Arlier, S., Mong, E. F., Lockhart, J., VanWye, J., Guzeloglu-Kayisli, O., Schatz, F., Magness, R. R., Lockwood, C. J., Tsibris, J. C. M., Kayisli, U. A., Totary-Jain, H. Decreased LIN28B in preeclampsia impairs human trophoblast differentiation and migration.
子痫前期 (PE) 是一种常见的产妇发病率原因，其特征为滋养层入侵和螺旋动脉转化受损，导致进行性胎盘缺氧。鉴于 LIN28A 和 LIN28B 在调节细胞代谢、分化和入侵方面的主要作用，我们假设 LIN28A 和/或 LIN28B 调节滋养层分化和入侵，其失调可能导致 PE。在这里，我们表明，LIN28B 在人类足月胎盘中的表达量比 LIN28A 高约 1300 倍，并且是原代人滋养层培养物中表达的主要同源物。与正常胎盘相比，妊娠期匹配的子痫前期胎盘的 LIN28B mRNA 和蛋白水平显著降低，而 LIN28A 表达没有差异。第一孕期人胎盘切片显示，在绒毛外 (侵袭性) 细胞滋养细胞和合体滋养细胞芽中，LIN28B 免疫反应性更强，而在绒毛滋养细胞中则较弱。LIN28B 过表达增加 HTR8 细胞增殖、迁移和侵袭，而 JEG3 细胞中的 LIN28B 敲低则减少细胞增殖。此外，JEG3 细胞中的 LIN28B 敲低抑制了合胞素 1 (SYN-1)、阿皮林受体早期内源性配体 (ELABELA) 和 19 号染色体 microRNA 簇，并增加了 ITGβ4 和 TNF-α 的 mRNA 表达。BeWo 和 JEG3 细胞在缺氧条件下孵育显著降低了 LIN28B 和 LIN28A、SYN-1 和 ELABELA 的表达，而 TNF-α 则增加。这些结果首次表明，LIN28B 是人类胎盘的主要同源物，LIN28B 的减少可能通过减少滋养层的入侵和融合，以及促进炎症，在 PE 中发挥作用。-Canfield, J., Arlier, S., Mong, E. F., Lockhart, J., VanWye, J., Guzeloglu-Kayisli, O., Schatz, F., Magness, R. R., Lockwood, C. J., Tsibris, J. C. M., Kayisli, U. A., Totary-Jain, H. 子痫前期中 LIN28B 的减少会损害人滋养层的分化和迁移。
