Center for Reproductive Medicine, Wuhan University Renmin Hospital, Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, Hubei, China.
Department of Dermatology, Wuhan University Renmin Hospital, Wuhan, Hubei, China.
J Cell Biochem. 2019 Aug;120(8):13243-13253. doi: 10.1002/jcb.28598. Epub 2019 Mar 19.
Pre-eclampsia (PE) is a leading cause of maternal and perinatal morbidity and mortality but the exact underlying mechanisms of PE pathogenesis remain elusive. Accumulated data suggested that the long noncoding RNAs (lncRNAs) play important roles in the pathogenesis of PE. The present study identified the changes of lncRNA Linc00261 in PE and its effects on trophoblasts invasion and migration. Our results showed that the expression of Linc00261 was upregulated in placental tissues of PE women compared with those of healthy pregnant women. Overexpression of Linc00261 suppressed cell invasion and migration, induced cell apoptosis, and caused cell-cycle arrest at G /G phase of HTR-8/SVneo cells; while knockdown of Linc00261 had the opposite effects on the HTR-8/SVneo cells. Mechanistic studies showed Linc00261 functioned as a competing endogenous RNA for miR-558 in HTR-8/SVneo cells, and miR-558 was negatively regulated by Linc00261. The expression level of miR-558 in the PE group was significantly lower than the control group, and the expression level of Linc00261 was negatively correlated with the expression level of miR-558 in the placental tissues of women with PE. Furthermore, miR-558 was found to negatively regulate the expression of TIMP metallopeptidase inhibitor 4 (TIMP4) via targeting the 3' untranslated region in the HTR-8/SVneo cells. Overexpression of miR-558 increased HTR-8/SVneo cell invasion and migration, which was attenuated by TIMP4 overexpression. More importantly, both overexpression of miR-558 and knockdown of TIMP4 partially reversed the suppressive effects of Linc00261 overexpression on cell invasion and migration of HTR-8/SVneo cells. Collectively, our results for the first time showed the upregulation of Linc00261 in the placental tissues of severe PE patients. The mechanistic results indicated that Linc00261 exerted the suppressive effects on the trophoblast invasion and migration via targeting miR-558/TIMP4 axis, which may involve in the pathogenesis of PE.
子痫前期 (PE) 是孕产妇和围生儿发病率和死亡率的主要原因，但 PE 发病机制的确切潜在机制仍不清楚。大量数据表明，长非编码 RNA (lncRNA) 在 PE 的发病机制中发挥重要作用。本研究鉴定了 PE 患者胎盘组织中 lncRNA Linc00261 的变化及其对滋养细胞侵袭和迁移的影响。我们的结果表明，与健康孕妇相比，PE 妇女胎盘组织中 Linc00261 的表达上调。Linc00261 的过表达抑制细胞侵袭和迁移，诱导细胞凋亡，并导致 HTR-8/SVneo 细胞停滞在 G1/G0 期；而 Linc00261 的敲低对 HTR-8/SVneo 细胞则有相反的影响。机制研究表明，Linc00261 在 HTR-8/SVneo 细胞中作为 miR-558 的竞争性内源性 RNA 发挥作用，miR-558 受 Linc00261 的负调控。PE 组 miR-558 的表达水平明显低于对照组，PE 患者胎盘组织中 Linc00261 的表达水平与 miR-558 的表达水平呈负相关。此外，发现 miR-558 通过靶向 HTR-8/SVneo 细胞的 3'UTR 负调控 TIMP 金属肽酶抑制剂 4 (TIMP4) 的表达。miR-558 的过表达增加了 HTR-8/SVneo 细胞的侵袭和迁移，而过表达 TIMP4 则减弱了这种作用。更重要的是，miR-558 的过表达和 TIMP4 的敲低均部分逆转了 Linc00261 过表达对 HTR-8/SVneo 细胞侵袭和迁移的抑制作用。综上所述，我们的研究结果首次表明，严重 PE 患者胎盘组织中 Linc00261 的表达上调。机制研究结果表明，Linc00261 通过靶向 miR-558/TIMP4 轴对滋养细胞的侵袭和迁移发挥抑制作用，这可能与 PE 的发病机制有关。
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