EIF5A1 promotes trophoblast migration and invasion via ARAF-mediated activation of the integrin/ERK signaling pathway.
EIF5A1 promotes trophoblast migration and invasion via ARAF-mediated activation of the integrin/ERK signaling pathway.
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EIF5A1通过ARAF介导的整合素/ERK信号通路激活促进滋养层迁移和侵袭
DOI：
10.1038/s41419-018-0971-5
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发表时间：
2018-09-11
影响因子：
9
通讯作者：
Lin Y
中科院分区：
文献类型：
--
作者：
Zhang J;Mo HQ;Tian FJ;Zeng WH;Liu XR;Ma XL;Li X;Qin S;Fan CF;Lin Y
滋养层功能障碍是复发性流产（RM）病因中涉及的一种机制。然而，滋养层功能的调节是复杂的，导致调节异常的机制仍有待阐明。在此，我们发现与健康对照相比，RM绒毛组织中的细胞滋养层中EIF5A1表达水平显著降低。以HTR - 8/SVneo细胞系作为模型系统，我们发现EIF5A1的过表达在体外促进滋养层增殖、迁移和侵袭。敲低EIF5A1或用N1 - 胍基 - 1,7 - 二氨基庚烷（GC7）抑制其羟腐胺赖氨酸化可抑制这些活动。同样，将EIF5A1突变为EIF5A1K50A以阻止羟腐胺赖氨酸化会消除其对增殖、迁移和侵袭的影响。此外，在绒毛外植体培养模型中，EIF5A1的上调增加了滋养层的生长，而敲低则有相反的效果。抑制EIF5A1的羟腐胺赖氨酸化也抑制外植体中滋养层的生长。从机制上讲，ARAF介导EIF5A1对滋养层迁移和侵袭的调节。羟腐胺赖氨酸化的EIF5A1通过控制ARAF的翻译来调节整合素/ERK信号通路。ARAF水平在RM绒毛组织的滋养层中也下调，并且ARAF的表达与EIF5A1呈正相关。总之，我们的结果表明EIF5A1可能是母胎界面滋养层功能的调节因子，EIF5A1和ARAF水平低可能与RM有关。
Trophoblast dysfunction is one mechanism implicated in the etiology of recurrent miscarriage (RM). Regulation of trophoblast function, however, is complex and the mechanisms contributing to dysregulation remain to be elucidated. Herein, we found EIF5A1 expression levels to be significantly decreased in cytotrophoblasts in RM villous tissues compared with healthy controls. Using the HTR-8/SVneo cell line as a model system, we found that overexpression of EIF5A1 promotes trophoblast proliferation, migration and invasion in vitro. Knockdown of EIF5A1 or inhibiting its hypusination with N1-guanyl-1,7-diaminoheptane (GC7) suppresses these activities. Similarly, mutating EIF5A1 to EIF5A1K50Ato prevent hypusination abolishes its effects on proliferation, migration and invasion. Furthermore, upregulation of EIF5A1 increases the outgrowth of trophoblasts in a villous explant culture model, whereas knockdown has the opposite effect. Suppression of EIF5A1 hypusination also inhibits the outgrowth of trophoblasts in explants. Mechanistically, ARAF mediates the regulation of trophoblast migration and invasion by EIF5A1. Hypusinated EIF5A1 regulates the integrin/ERK signaling pathway via controlling the translation of ARAF. ARAF level is also downregulated in trophoblasts of RM villous tissues and expression of ARAF is positively correlated with EIF5A1. Together, our results suggest that EIF5A1 may be a regulator of trophoblast function at the maternal–fetal interface and low levels of EIF5A1 and ARAF may be associated with RM.
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影响因子：
16.6
作者：
Desrochers LM;Bordeleau F;Reinhart-King CA;Cerione RA;Antonyak MA
通讯作者：
Antonyak MA
影响因子：
4
作者：
Na, Kyu-Hwan;Lee, Hyun-Jung;Kim, Gi-Jin
通讯作者：
Kim, Gi-Jin
影响因子：
4.8
作者：
Mahon, ES;Hawrysh, AD;Anderson, DH
通讯作者：
Anderson, DH
影响因子：
3.5
作者：
Park, M. H.;Nishimura, K.;Zanelli, C. F.;Valentini, S. R.
通讯作者：
Valentini, S. R.
影响因子：
7.3
作者：
Mooz, Juliane;Oberoi-Khanuja, Tripat Kaur;Rajalingam, Krishnaraj
通讯作者：
Rajalingam, Krishnaraj