Self-control of HGF regulation on human trophoblast cell invasion via enhancing c-Met receptor shedding by ADAM10 and ADAM17

J Clin Endocrinol Metab. 2012 Aug;97(8):E1390-401. doi: 10.1210/jc.2012-1150. Epub 2012 Jun 11.


Context: 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.

Objectives and design: 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.

Results: 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.

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / physiology*
  • ADAM10 Protein
  • ADAM17 Protein
  • Adult
  • Amyloid Precursor Protein Secretases / physiology*
  • Female
  • Hepatocyte Growth Factor / physiology*
  • Humans
  • Hydrogen Peroxide / pharmacology
  • MAP Kinase Signaling System / physiology
  • Membrane Proteins / physiology*
  • Pre-Eclampsia / etiology
  • Pregnancy
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-met / physiology*
  • Trophoblasts / metabolism*
  • Trophoblasts / pathology


  • HGF protein, human
  • Membrane Proteins
  • Hepatocyte Growth Factor
  • Hydrogen Peroxide
  • Proto-Oncogene Proteins c-met
  • Proto-Oncogene Proteins c-akt
  • Amyloid Precursor Protein Secretases
  • ADAM Proteins
  • ADAM10 Protein
  • ADAM10 protein, human
  • ADAM17 Protein
  • ADAM17 protein, human