TY - JOUR
T1 - Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesis
AU - Fernandez-Zapico, Martin E.
AU - Gonzalez-Paz, Natalia C.
AU - Weiss, Ellen
AU - Savoy, Doris N.
AU - Molina, Julian R.
AU - Fonseca, Rafael
AU - Smyrk, Thomas C.
AU - Chari, Suresh T.
AU - Urrutia, Raul
AU - Billadeau, Daniel D.
N1 - Funding Information:
We would like to thank Dr. Matsuda for the pRaichu-Rho family biosensors and Scott Van Wier and Linda Wellik for the technical assistance with FISH analysis and immunohistochemistry. We would also like to thank Dr. D.A. Tuveson for the pancreatic tissue sections from the KRAS G12D mouse. This work was supported by the Lustgarten Foundation for Pancreatic Cancer Research and the National Institute of Health grants DK52913 and DK56620 (R.U.), Specialized Program of Research Excellence grant P50-CA102701 (D.D.B. and R.U.), Public Health Service grant number R01 CA83724-01, the Fund to Cure Myeloma (R.F.), and the Mayo Clinic. D.D.B. is a recipient of a Cancer Research Institute Investigator Award. R.F. is a Clinical Investigator of the Damon Runyon Cancer Research Fund.
PY - 2005/1
Y1 - 2005/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ccr.2004.11.024
DO - 10.1016/j.ccr.2004.11.024
M3 - Article
C2 - 15652748
AN - SCOPUS:19944432938
SN - 1535-6108
VL - 7
SP - 39
EP - 49
JO - Cancer cell
JF - Cancer cell
IS - 1
ER -