State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
J Clin Endocrinol Metab. 2012 Aug;97(8):E1390-401. doi: 10.1210/jc.2012-1150. Epub 2012 Jun 11.
Hepatocyte growth factor (HGF)/c-Met signaling has been implicated in mammalian placental development. Integral c-Met can be released from endothelial cell membrane by proteolysis to form a soluble, truncated protein [soluble Met (sMet)], which is biochemically able to bind HGF and may disrupt HGF/c-Met signaling. By far, production of sMet in human placenta has not been reported, and the shedding mechanism remains unclear.
In this study, production of sMet in healthy pregnant placenta and preeclamptic ones was compared, and the role of sMet on trophoblast cell invasion as well as the regulation of c-Met shedding by HGF were investigated in an immortal trophoblast cell line, B6Tert-1.
Placenta productions of sMet, pro- and active forms of a disintegrin and metalloprotease 10 (ADAM10) and ADAM17 in preeclamptic patients were significantly higher than those in normal pregnant women. In B6Tert-1 cells, the HGF-induced promotion on cell invasion and activation of MAPK and AKT could be extensively blocked by sMet. ADAM10 and ADAM17, but not ADAM12, were explored to be sheddases of c-Met. HGF down-regulated c-Met receptor expression, whereas it up-regulated pro- and active/mature forms of ADAM10 and ADAM17 expression, which resulted in enhanced sMet production. Stimulation of H(2)O(2) caused an increase in active ADAM10, pro-ADAM17, and active ADAM17 levels and thus excessive c-Met shedding.
HGF could negatively self-control its regulatory effect on trophoblast cell invasion via enhancing proteolysis of its receptor. Unbalancing of HGF self-control by oxidative stress may lead to impeding placentation in relevance to preeclampsia.
肝细胞生长因子（HGF）/c-Met 信号通路参与哺乳动物胎盘发育。完整的 c-Met 可通过蛋白水解从血管内皮细胞膜上释放出来，形成一种可溶性的、截断的蛋白质[可溶性 Met（sMet）]，它在生化上能够结合 HGF，并可能破坏 HGF/c-Met 信号通路。到目前为止，尚未有报道称人胎盘中存在 sMet 的产生，其脱落机制尚不清楚。
本研究比较了健康孕妇胎盘和子痫前期胎盘 sMet 的产生，并在永生化滋养细胞系 B6Tert-1 中研究了 sMet 对滋养细胞侵袭的作用以及 HGF 对 c-Met 脱落的调节作用。
子痫前期患者胎盘 sMet、前蛋白和金属蛋白酶 10（ADAM10）和 ADAM17 的产生明显高于正常孕妇。在 B6Tert-1 细胞中，HGF 诱导的细胞侵袭促进作用和 MAPK 和 AKT 的激活可被 sMet 广泛阻断。ADAM10 和 ADAM17，但不是 ADAM12，被发现是 c-Met 的脱落酶。HGF 下调 c-Met 受体表达，而上调前蛋白和成熟/成熟形式的 ADAM10 和 ADAM17 表达，导致 sMet 产生增加。H2O2 的刺激导致活性 ADAM10、前 ADAM17 和活性 ADAM17 水平增加，从而导致 c-Met 过度脱落。
HGF 可以通过增强其受体的蛋白水解来负自我调控其对滋养细胞侵袭的调节作用。氧化应激对 HGF 自我调控的不平衡可能导致与子痫前期相关的胎盘形成障碍。
