Hepatocyte growth factor-mediated cell invasion in pancreatic cancer cells is dependent on neuropilin-1

Cancer Res. 2007 Nov 1;67(21):10309-16. doi: 10.1158/0008-5472.CAN-07-3256.


Neuropilin-1 (Np-1), a receptor for semaphorin 3A and vascular endothelial growth factor, is expressed at high levels in pancreatic ductal adenocarcinoma (PDAC). To assess the potential role of Np-1 in PDAC, COLO-357 pancreatic cancer cells, which express relatively low levels of Np-1, were stably transfected with the Np-1 cDNA. Np-1 overexpression was associated with enhanced cell invasiveness in response to hepatocyte growth factor (HGF), and this effect was abolished by small interfering RNA-mediated down-regulation of c-Met. Conversely, in PANC-1 pancreatic cancer cells, which express relatively high levels of Np-1, suppression of endogenous Np-1 completely abolished HGF-mediated cell invasion. To determine which pathways are involved in Np-1-mediated facilitation of c-Met-dependent cell invasiveness, the effects of HGF on signaling were examined next in sham-transfected and Np-1-overexpressing COLO-357 cells. HGF actions on c-Met tyrosine phosphorylation and p38 mitogen-activated protein kinase (MAPK) activation were increased in Np-1-overexpressing COLO-357 cells by comparison with HGF effects in sham-transfected cells. SB203580, an inhibitor of p38 MAPK, suppressed HGF-induced invasion in Np-1-overexpressing cells, whereas U0126, a MAP/extracellular signal-regulated kinase kinase inhibitor, was without effect. PP2, a Src inhibitor, and LY294002, a phosphatidylinositol 3-kinase inhibitor, also suppressed HGF-induced invasion in these cells. Immunoprecipitation studies revealed that Np-1 associated with c-Met, but not with epidermal growth factor receptor, family members. Confocal microscopy indicated that this association occurred on the plasma membrane and that HGF promoted the internalization of Np-1-c-Met complex, leading to its perinuclear localization. These findings indicate that Np-1 is required for efficient activation of c-Met-dependent pathways that promote cell invasiveness.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line, Tumor
  • Hepatocyte Growth Factor / pharmacology*
  • Humans
  • Neoplasm Invasiveness
  • Neuropilin-1 / analysis
  • Neuropilin-1 / physiology*
  • Pancreatic Neoplasms / pathology*
  • Phosphatidylinositol 3-Kinases / physiology
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / physiology
  • Proto-Oncogene Proteins c-met / physiology
  • Signal Transduction
  • p38 Mitogen-Activated Protein Kinases / physiology


  • Neuropilin-1
  • Hepatocyte Growth Factor
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-met
  • Proto-Oncogene Proteins c-akt
  • p38 Mitogen-Activated Protein Kinases