Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesis
| Autor: | Doris N. Savoy, Natalia Gonzalez-Paz, Rafael Fonseca, Ellen A. Weiss, Martin E. Fernandez-Zapico, Daniel D. Billadeau, Raul Urrutia, Suresh T. Chari, Julian R. Molina, Thomas C. Smyrk |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Male
rac1 GTP-Binding Protein Cancer Research Recombinant Fusion Proteins Mice Nude RAC1 Cell Cycle Proteins Biology Adenocarcinoma Protein Serine-Threonine Kinases medicine.disease_cause 03 medical and health sciences Mice 0302 clinical medicine Cyclin D1 Downregulation and upregulation Pancreatic tumor Pancreatic cancer Cell Line Tumor Proto-Oncogene Proteins medicine Animals Humans Promoter Regions Genetic Proto-Oncogene Proteins c-vav 030304 developmental biology Cell Proliferation 0303 health sciences Epidermal Growth Factor Cell Biology DNA Methylation medicine.disease 3. Good health Pancreatic Neoplasms Survival Rate Cell Transformation Neoplastic p21-Activated Kinases Oncology 030220 oncology & carcinogenesis Cancer research Ectopic expression Signal transduction Carcinogenesis Signal Transduction |
| Zdroj: | Cancer Cell. 7(1):39-49 |
| ISSN: | 1535-6108 |
| DOI: | 10.1016/j.ccr.2004.11.024 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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