Luo Rongcan, Shao Xuan, Xu Peng, Liu Yanlei, Wang Yongqing, Zhao Yangyu, Liu Ming, Ji Lei, Li Yu-Xia, Chang Cheng, Qiao Jie, Peng Chun, Wang Yan-Ling
From the State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (R.L., X.S., P.X., Y.L., M.L., L.J., Y.-x.L., Y.-l.W.); School of Life Sciences, Lanzhou University, Lanzhou, China (R.L., C.C.); Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China (Y.W., Y.Z., J.Q.); Department of Biology, York University, Toronto, Ontario, Canada (C.P.); and University of Chinese Academy of Sciences, Beijing, China (X.S., P.X., Y.L.).
Hypertension. 2014 Oct;64(4):839-45. doi: 10.1161/HYPERTENSIONAHA.114.03530. Epub 2014 Jun 30.
Preeclampsia is a pregnancy-specific syndrome manifested by the onset of hypertension and proteinuria after the 20th week of gestation. Abnormal placenta development has been generally accepted as the initial cause of the disorder. Recently, microRNA-210 (miR-210) has been found to be upregulated in preeclamptic placentas compared with normal placentas, indicating a possible association of this small molecule with the placental pathology of preeclampsia. However, the function of miR-210 in the development of the placenta remains elusive. The aim of this study was to characterize the molecular mechanism of preeclampsia development by examining the role of miR-210. In this study, miR-210 and potassium channel modulatory factor 1 (KCMF1) expressions were compared in placentas from healthy pregnant individuals and patients with preeclampsia, and the role of miR-210 in trophoblast cell invasion via the downregulation of KCMF1 was investigated in the immortal trophoblast cell line HTR8/SVneo. The levels of KCMF1 were significantly lower in preeclamptic placenta tissues than in gestational week-matched normal placentas, which was inversely correlated with the level of miR-210. KCMF1 was validated as the direct target of miR-210 using real-time polymerase chain reaction, Western blotting, and dual luciferase assay in HTR8/SVneo cells. miR-210 inhibited the invasion of trophoblast cells, and this inhibition was abrogated by the overexpression of KCMF1. The inflammatory factor tumor necrosis factor-α could upregulate miR-210 while suppressing KCMF1 expression in HTR8/SVneo cells. This is the first report on the function of KCMF1 in human placental trophoblast cells, and the data indicate that aberrant miR-210 expression may contribute to the occurrence of preeclampsia by interfering with KCMF1-mediated signaling in the human placenta.
子痫前期是一种妊娠特异性综合征，表现为妊娠20周后出现高血压和蛋白尿。胎盘发育异常已被普遍认为是该疾病的初始病因。最近，与正常胎盘相比，发现子痫前期胎盘中的微小RNA-210（miR-210）上调，表明这种小分子可能与子痫前期的胎盘病理有关。然而，miR-210在胎盘发育中的功能仍不清楚。本研究的目的是通过研究miR-210的作用来阐明子痫前期发展的分子机制。在本研究中，比较了健康孕妇和子痫前期患者胎盘组织中miR-210和钾通道调节因子1（KCMF1）的表达，并在永生化滋养层细胞系HTR8/SVneo中研究了miR-210通过下调KCMF1对滋养层细胞侵袭的作用。子痫前期胎盘组织中KCMF1的水平显著低于孕周匹配的正常胎盘，且与miR-210水平呈负相关。在HTR8/SVneo细胞中，通过实时聚合酶链反应、蛋白质印迹和双荧光素酶测定验证KCMF1是miR-210的直接靶点。miR-210抑制滋养层细胞的侵袭，而KCMF1的过表达可消除这种抑制作用。炎症因子肿瘤坏死因子-α可上调HTR8/SVneo细胞中miR-210的表达，同时抑制KCMF1的表达。这是关于KCMF1在人胎盘滋养层细胞中功能的首次报道，数据表明miR-210表达异常可能通过干扰人胎盘中KCMF1介导的信号传导导致子痫前期的发生。
