Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesis

Cancer Cell. 2005 Jan;7(1):39-49. doi: 10.1016/j.ccr.2004.11.024.

Abstract

Herein, we show that the hematopoietic-specific GEF VAV1 is ectopically expressed in primary pancreatic adenocarcinomas due to demethylation of the gene promoter. Interestingly, VAV1-positive tumors had a worse survival rate compared to VAV1-negative tumors. Surprisingly, even in the presence of oncogenic KRAS, VAV1 RNAi abrogates neoplastic cellular proliferation in vitro and in vivo, thus identifying Vav1 as a growth-stimulatory protein in this disease. Vav1 acts synergistically with the EGF receptor to stimulate pancreatic tumor cell proliferation. Mechanistically, the effects of Vav1 require its GEF activity and the activation of Rac1, PAK1, and NF-kappaB and involve cyclin D1 upregulation. Thus, the discovery of prooncogenic pathways regulated by Vav1 makes it an attractive target for therapeutic intervention.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / mortality
  • Adenocarcinoma / pathology
  • Adenocarcinoma / physiopathology
  • Animals
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic*
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • DNA Methylation
  • Epidermal Growth Factor / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / mortality
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / physiopathology
  • Promoter Regions, Genetic
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-vav
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • Survival Rate
  • p21-Activated Kinases
  • rac1 GTP-Binding Protein / metabolism

Substances

  • Cell Cycle Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-vav
  • Recombinant Fusion Proteins
  • VAV1 protein, human
  • Vav1 protein, mouse
  • Cyclin D1
  • Epidermal Growth Factor
  • PAK1 protein, human
  • Pak1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • p21-Activated Kinases
  • rac1 GTP-Binding Protein