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

Martin E. Fernandez-Zapico, Natalia C. Gonzalez-Paz, Ellen Weiss, Doris N. Savoy, Julian R. Molina, Rafael Fonseca, Thomas C. Smyrk, Suresh T. Chari, Raul Urrutia, Daniel D. Billadeau

Research output: Contribution to journalArticle

152 Scopus citations

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-κB and involve cyclin D1 upregulation. Thus, the discovery of prooncogenic pathways regulated by Vav1 makes it an attractive target for therapeutic intervention.

Original languageEnglish (US)
Pages (from-to)39-49
Number of pages11
JournalCancer cell
Volume7
Issue number1
DOIs
StatePublished - Jan 1 2005

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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