Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesis. Cancer Cell 2005 Jan;7(1):39-49
Date
01/18/2005Pubmed ID
15652748DOI
10.1016/j.ccr.2004.11.024Scopus ID
2-s2.0-19944432938 (requires institutional sign-in at Scopus site) 178 CitationsAbstract
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.
Author List
Fernandez-Zapico ME, Gonzalez-Paz NC, Weiss E, Savoy DN, Molina JR, Fonseca R, Smyrk TC, Chari ST, Urrutia R, Billadeau DDAuthor
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdenocarcinomaAnimals
Cell Cycle Proteins
Cell Line, Tumor
Cell Proliferation
Cell Transformation, Neoplastic
Cyclin D1
DNA Methylation
Epidermal Growth Factor
Humans
Male
Mice
Mice, Nude
Pancreatic Neoplasms
Promoter Regions, Genetic
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-vav
Recombinant Fusion Proteins
Signal Transduction
Survival Rate
p21-Activated Kinases
rac1 GTP-Binding Protein