Cartwright Judith E, Tse Wai Kwan, Whitley Guy StJ
Department of Biochemistry and Immunology, St. George's Hospital Medical School, Cranmer Terrace, London, SW17 ORE, United Kingdom.
Exp Cell Res. 2002 Oct 1;279(2):219-26. doi: 10.1006/excr.2002.5616.
Hepatocyte growth factor (HGF) increases human trophoblast motility and invasion, an effect which is abrogated when inducible nitric oxide synthase (iNOS) is inhibited. In this study we have investigated the pathways involved in the regulation of trophoblast motility. Both basal and HGF-stimulated motility of the extravillous trophoblast cell line, SGHPL-4, were inhibited in a dose-dependent manner by the phosphatidylinositol-3-kinase (PI3-kinase) inhibitor, LY294002. HGF-stimulated iNOS expression was also inhibited by LY294002 and direct activation of PI3-kinase, using the peptide 740Y-P, led to an increase in iNOS expression and cell motility. Pretreatment with rapamycin, which acts at a point distal to PI3-kinase activation, also inhibited basal and HGF-stimulated motility. Inhibition of the p42/p44 mitogen activated protein kinase (MAPK) pathway but not the p38 MAPK pathway had significant inhibitory effects on HGF-stimulated but not basal trophoblast motility. Inhibition of p42/p44 MAPK also inhibited HGF-induced iNOS expression. This data demonstrate that the PI3-kinase signaling pathway is involved in basal trophoblast motility and that both MAPK and PI3-kinase signaling pathways are important in HGF-stimulated motility and iNOS expression.
肝细胞生长因子（HGF）可增加人滋养层细胞的运动性和侵袭能力，而当诱导型一氧化氮合酶（iNOS）受到抑制时，该效应即被消除。在本研究中，我们调查了参与调节滋养层细胞运动性的信号通路。磷脂酰肌醇-3-激酶（PI3-激酶）抑制剂LY294002以剂量依赖的方式抑制了绒毛外滋养层细胞系SGHPL-4的基础运动性和HGF刺激的运动性。LY294002还抑制了HGF刺激的iNOS表达，并且使用肽740Y-P直接激活PI3-激酶会导致iNOS表达增加和细胞运动性增强。用雷帕霉素预处理（作用于PI3-激酶激活的远端位点）也抑制了基础运动性和HGF刺激的运动性。抑制p42/p44丝裂原活化蛋白激酶（MAPK）信号通路而非p38 MAPK信号通路，对HGF刺激的而非基础的滋养层细胞运动性具有显著抑制作用。抑制p42/p44 MAPK也抑制了HGF诱导的iNOS表达。这些数据表明，PI3-激酶信号通路参与基础滋养层细胞运动性，并且MAPK和PI3-激酶信号通路在HGF刺激的运动性和iNOS表达中均很重要。
