Let-7i-Induced Atg4B Suppression Is Essential for Autophagy of Placental Trophoblast in Preeclampsia
Let-7i-Induced Atg4B Suppression Is Essential for Autophagy of Placental Trophoblast in Preeclampsia
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Let-7i 诱导的 Atg4B 抑制对于先兆子痫胎盘滋养层自噬至关重要
DOI：
10.1002/jcp.25661
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发表时间：
2017
影响因子：
5.6
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Xu Yinyan;Huang Xinyan;Xie Juan;Chen Yanni;Fu Jing;Wang Li;Xu YY;Wang L
自噬被鉴定为II型程序性细胞死亡，已经知道参与先兆子痫（PE）的病理生理学，先兆子痫是一种高发病率的妊娠疾病。本研究旨在探讨let-7i（一种miRNA）在滋养细胞自噬中的功能作用。本研究中使用的胎盘组织收集自重度先兆子痫（SPE）患者或正常孕妇。SPE患者胎盘组织let-7 i水平降低。此外，在SPE中观察到自噬空泡，微管相关蛋白1轻链3（LC 3）II/I的表达升高。在体外，let-7 i模拟物抑制人HTR-8/SVneo滋养层细胞系（HTR-8）和人胎盘绒毛膜癌细胞系JEG-3中的自噬活性，而let-7 i抑制剂增强活性。自噬相关的4 B半胱氨酸肽酶（Atg 4 B）作为let-7i的潜在靶点，在SPE中的表达水平增加。正如预期的那样，使用双荧光素酶报告基因测定，Atg 4 B的表达增加受到let-7i的负调控。此外，这些用let-7i模拟物或抑制剂转染的滋养层样细胞导致Atg 4 B在mRNA和蛋白水平上的显著变化。更重要的是，Atg 4 B过表达可以部分逆转let-7i模拟降低的LC 3 II/I水平;而Atg 4 B沉默部分减弱let-7i抑制剂诱导的LC 3 II/I表达水平。总之，这些发现表明let-7i能够通过调节Atg 4 B表达来调节自噬活性，这可能有助于PE的发病机制。J.细胞。232：2581-2589，2017。© 2016 Wiley Periodicals，Inc.
Autophagy, identified as type II programmed cell death, has already been known to be involved in the pathophysiology of preeclampsia (PE), which is a gestational disease with high morbidity. The present study aims to investigate the functional role of let‐7i, a miRNA, in trophoblastic autophagy. Placental tissue used in this study was collected from patients with severe preeclampsia (SPE) or normal pregnant women. A decreased level of let‐7i was found in placenta of SPE. In addition, autophagic vacuoles were observed in SPE and the expression of microtubule associated protein 1 light chain 3 (LC3) II/I was elevated. In vitro, let‐7i mimics suppressed the autophagic activities in human HTR‐8/SVneo trophoblast cell line (HTR‐8) and human placental choriocarcinoma cell line JEG‐3, whereas let‐7i inhibitor enhanced the activities. As a potential target of let‐7i, autophagy‐related 4B cysteine peptidase (Atg4B) had an increased expression level in SPE. As expected, the increased expression of Atg4B was negatively regulated by let‐7i using dual luciferase reporter assay. Furthermore, these trophoblast‐like cells transfected with the let‐7i mimic or inhibitors resulted in a significant change of Atg4B in both mRNA and protein level. More importantly, Atg4B overexpression could partly reverse let‐7i mimic‐reduced LC3II/I levels; whereas Atg4B silencing partly attenuated let‐7i inhibitor‐induced the level of LC3II/I expression. Taken together, these findings suggest that let‐7i is able to regulate autophagic activity via regulating Atg4B expression, which might contribute to the pathogenesis of PE. J. Cell. Physiol. 232: 2581–2589, 2017. © 2016 Wiley Periodicals, Inc.