Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesis.
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.
Fernandez-Zapico
Martin E
ME
Gastroenterology Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Gonzalez-Paz
Natalia C
NC
Weiss
Ellen
E
Savoy
Doris N
DN
Molina
Julian R
JR
Fonseca
Rafael
R
Smyrk
Thomas C
TC
Chari
Suresh T
ST
Urrutia
Raul
R
Billadeau
Daniel D
DD
D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004815:Epidermal Growth Factor / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015996:Survival Rate; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D018797:Cell Cycle Proteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011993:Recombinant Fusion Proteins; C496618:VAV1 protein, human; C496619:Vav1 protein, mouse; D019938:Cyclin D1; D004815:Epidermal Growth Factor; C515903:PAK1 protein, human; C515905:Pak1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein