This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Qiu, Q Articles by Gruslin, A Search for Related Content PubMed PubMed Citation Articles by Qiu, Q Articles by Gruslin, A

EGF-induced trophoblast secretion of MMP-9 and TIMP-1 involves activation of both PI3K and MAPK signalling pathways

¹ Hormones, Growth and Development Program, Ottawa Health Research Institute, Ottawa, Ontario, Canada K1Y 4E9, ² Divisions of Maternal-Fetal Medicine and ³ Reproductive Medicine, Department of Obstetrics and Gynaecology, University of Ottawa, The Ottawa Hospital, Ottawa, Ontario, Canada K1H 8L6

Correspondence should be addressed to A Gruslin; Email: agruslin{at}ottawahospital.on.ca

Epidermal growth factor (EGF) is present in the maternal-fetal environment and has an important role in placental development. Matrix metalloproteinase-9 (MMP-9) expression/activation is a pre-requisite in extravillous trophoblast invasion. Whereas EGF up-regulates MMP-9 activity in a variety of cell types, there is no direct evidence for the stimulation of MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) secretion by EGF in extravillous trophoblasts. In addition, the signalling pathways involved in this regulation are not clear. In the present study, we have examined the possible involvement of the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways in the regulation of the MMP-9/TIMP-1 system by EGF in vitro. We used a well-established invasive extravillous trophoblast cell line (HTR8/Svneo) and measured gene and protein expression by semi-quantitative RT-PCR and western analysis respectively. MMP activity was determined by zymography. We showed for the first time that EGF activated both PI3K/Akt and MAPK/extracellular-signal regulated kinase (ERK) signalling in HTR8/SVneo, and increased both MMP-9 and TIMP-1 mRNAs and protein concentrations. Interfering with either signalling pathway via PI3K inhibitor LY294002 or MEK inhibitor U0126 in EGF-stimulated HTR8/SVneo cells blocked the induction of MMP-9 and TIMP-1. LY294002 inhibited Akt phosphorylation, but had no effect on ERK phosphorylation; U0126 suppressed ERK phosphorylation without interfering with the phosphorylation of Akt. In addition, expression of constitutively active Akt (Myr-Akt1, Myr-Akt2, Myr-Akt3) was not sufficient to induce proMMP-9 and TIMP-1 secretion. Our results suggest that the activation of both PI3K and MAPK pathways in extravillous trophoblasts is necessary for the up-regulation of MMP-9 and TIMP-1 expression by EGF.

This article has been cited by other articles:

				F. C. Denison, S. Battersby, A. E. King, M. Szuber, and H. N. Jabbour Prokineticin-1: A Novel Mediator of the Inflammatory Response in Third-Trimester Human Placenta Endocrinology, July 1, 2008; 149(7): 3470 - 3477. [Abstract] [Full Text] [PDF]

				J. Prast, L. Saleh, H. Husslein, S. Sonderegger, H. Helmer, and M. Knofler Human Chorionic Gonadotropin Stimulates Trophoblast Invasion through Extracellularly Regulated Kinase and AKT Signaling Endocrinology, March 1, 2008; 149(3): 979 - 987. [Abstract] [Full Text] [PDF]

				K. Handschuh, J. Guibourdenche, V. Tsatsaris, M. Guesnon, I. Laurendeau, D. Evain-Brion, and T. Fournier Human Chorionic Gonadotropin Produced by the Invasive Trophoblast But Not the Villous Trophoblast Promotes Cell Invasion and Is Down-Regulated by Peroxisome Proliferator-Activated Receptor-{gamma} Endocrinology, October 1, 2007; 148(10): 5011 - 5019. [Abstract] [Full Text] [PDF]

				W.-H. Zhou, M.-R. Du, L. Dong, X.-Y. Zhu, J.-Y. Yang, Y.-Y. He, and D.-J. Li Cyclosporin A increases expression of matrix metalloproteinase 9 and 2 and invasiveness in vitro of the first-trimester human trophoblast cells via the mitogen-activated protein kinase pathway Hum. Reprod., October 1, 2007; 22(10): 2743 - 2750. [Abstract] [Full Text] [PDF]

				C. Ferretti, L. Bruni, V. Dangles-Marie, A.P. Pecking, and D. Bellet Molecular circuits shared by placental and cancer cells, and their implications in the proliferative, invasive and migratory capacities of trophoblasts Hum. Reprod. Update, March 1, 2007; 13(2): 121 - 141. [Abstract] [Full Text] [PDF]