Long non-coding RNA DLX6-AS1 is upregulated in preeclampsia and modulates migration and invasion of trophoblasts through the miR-376c/GADD45A axis
Long non-coding RNA DLX6-AS1 is upregulated in preeclampsia and modulates migration and invasion of trophoblasts through the miR-376c/GADD45A axis
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DOI：
10.1016/j.yexcr.2018.07.039
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发表时间：
2018-09-15
影响因子：
3.7
通讯作者：
Wang, Chenhong
中科院分区：
文献类型：
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作者：
Tan, Yan;Xiao, Di;Wang, Chenhong
长链非编码RNA（lncRNA）是参与多种生物过程和人类疾病（包括先兆子痫）的关键调节分子。然而，它们在先兆子痫进展中的表达和功能在很大程度上仍不清楚。在这项研究中，与正常对照相比，lncRNA DLX 6-AS 1在先兆子痫患者的胎盘中被证实显著上调。DLX 6-AS 1的过表达显著降低滋养层细胞JEG 3和HTR-8/SVneo的增殖、迁移和侵袭。荧光素酶活性和RNA pull-down分析显示DLX 6-AS 1与miR-376 c相互作用，并且DLX 6-AS 1的过表达显著降低了HTR-8/SVneo细胞中miR-376 c的表达。此外，miR-376 c在HTR-8/SVneo细胞中靶向并下调GADD 45 A。GADD 45 A的过表达有效地减弱了miR-376 c诱导的HTR-8/SVneo细胞增殖、迁移和侵袭的增加。进一步的研究表明，DLX 6-AS 1诱导的滋养层细胞增殖、迁移和侵袭的抑制被GADD 45 A敲低和miR-376 c过表达有效地中和。总之，这些发现表明DLX 6-AS 1可能通过miR-376 c/GADD 45 A轴损害滋养层细胞的增殖、迁移和侵袭能力而导致先兆子痫。
Long non-coding RNA (lncRNA) are key regulatory molecules that are implicated in diverse biological processes and human diseases, including preeclampsia. However, their expression and functions in the progression of preeclampsia remains largely unclear. In this study, lncRNA DLX6-AS1 was confirmed to be significantly upregulated in the placentas of patients with preeclampsia, compared with normal controls. Overexpression of DLX6-AS1 dramatically decreased proliferation, migration and invasion in trophoblast JEG3 and HTR-8/SVneo cells. Luciferase activity and RNA pull-down assays showed that DLX6-AS1 interacted with miR-376c, and that overexpression of DLX6-AS1 significantly reduced expression of miR-376c in HTR-8/SVneo cells. Also, miR-376c targeted and downregulated GADD45A in HTR-8/SVneo cells. Overexpression of GADD45A effectively attenuated a miR-376c-induced increase in the proliferation, migration and invasion of HTR-8/SVneo cells. Further research showed that DLX6-AS1-induced inhibition of trophoblast proliferation, migration and invasion was effectively neutralized by GADD45A knockdown and miR-376c overexpression. Taken together, these findings suggest that DLX6-AS1 may contribute to preeclampsia by impairing proliferative, migratory and invasive abilities of trophoblasts via the miR-376c/GADD45A axis.