Journal
LIFE SCIENCES
Volume 236, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2019.116899
Keywords
Amphiregulin; HTR-8/SVneo cell; MMP9/TIMP-1 ratio; Invasiveness; ERK1/2; Akt
Funding
- National Natural Science Foundation of China [81820108016, 81601253]
- specific fund of clinical medical research of Chinese Medical Association [16020160632]
- china scholarship council
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Aims: The aim of our study is to illustrate the role of amphiregulin in trophoblast invasiveness and underlying signal cascades. Main methods: An 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 findings: Our 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. Significance: ERK1/2 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.
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