Amphiregulin promotes trophoblast invasion and increases MMP9/TIMP1 ratio through ERK1/2 and Akt signal pathways
Amphiregulin promotes trophoblast invasion and increases MMP9/TIMP1 ratio through ERK1/2 and Akt signal pathways
复制标题
双调蛋白通过 ERK1/2 和 Akt 信号通路促进滋养层侵袭并增加 MMP9/TIMP1 比值
DOI：
10.1016/j.lfs.2019.116899
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发表时间：
2019
期刊：
影响因子：
6.1
通讯作者：
Sun Yingpu
中科院分区：
文献类型：
--
作者：
Yu Yiping;Fang Lanlan;Wang Sijia;Li Yiran;Guo Yanjie;Sun Yingpu
目的本研究旨在阐明双调节素在滋养层细胞侵袭和信号转导中的作用。采用Matrigel-Transwell侵袭实验检测双调蛋白对细胞侵袭能力的影响。RT-qPCR和酶谱分析检测MMP9和MMP2mRNA的表达水平和活性。我们的结果表明，两调蛋白能在不干扰细胞增殖的情况下促进HTR-8/SVneo细胞的侵袭性，并显著上调MMP9和TIMP-1mRNAs的表达以及MMP9/TIMP-1的比值。使用MEK和PI3K信号的特异性抑制剂进一步表明，ERK1/2和Akt信号通路都是两调蛋白诱导的细胞侵袭所必需的。MMP9的表达上调需要ERK1/2和Akt信号通路的协同作用，而TIMP-1mRNA的上调更需要ERK1/2的协同作用。同时，我们首次提出通过上调表皮生长因子受体(EGFR)和肝素结合EGF(HB-EGF)mRNA.ERK1/2和Akt信号通路介导了两调蛋白诱导的MMP9 mRNA和MMP9/TIMP-1比值的上调，从而促进了HTR-8/SVneo细胞的侵袭。
AimsThe aim of our study is to illustrate the role of amphiregulin in trophoblast invasiveness and underlying signal cascades.Main methodsAn immortalized human early extravillous cell line, HTR-8/SVneo, was used for this investigation. Matrigel-transwell invasion assay was used for testing the effects of amphiregulin on cell invasiveness. MMP9 and MMP2 mRNA expression level and activity were measured using Rt-qPCR and zymographic analysis. Cell signals involved in the invasion process were verified using western blot and specific inhibitors.Key findingsOur results showed that amphiregulin could promote HTR-8/SVneo cell invasiveness without interfering cell proliferation, and significantly upregulate the expression of MMP9 and TIMP-1 mRNAs as well as the ratio of MMP9/TIMP-1. Using specific inhibitors for MEK and PI3K signaling further indicated that, both ERK1/2 and Akt signal pathways were required for amphiregulin-induced cell invasiveness. The co-ordination between ERK1/2 and Akt signaling pathway was needed for the upregulation of MMP9 mRNA, while ERK1/2 was more essential for the upregulation of TIMP-1 mRNA. Meanwhile, we first put forward that the deficiency of amphiregulin expression in trophoblast might be compensated by the upregulation of epidermal growth factor receptor (EGFR) and heparin-binding EGF (HB-EGF) mRNA.SignificanceERK1/2 and Akt signaling pathways mediate amphiregulin-induced upregulation of MMP9 mRNA and the MMP9/TIMP-1 ratio, which subsequently contribute to amphiregulin-promotion of HTR-8/SVneo cell invasion.