FGFR4 Role in epithelial-mesenchymal transition and its therapeutic value in colorectal cancer
Publisher
Public Library of ScienceDate
2013-05-16Citation
10.1371/journal.pone.0063695
PLoS One 8.5 (2013): e63695
ISSN
1932-6203DOI
10.1371/journal.pone.0063695Funded by
This research was supported by grant BIO2009-08818 from the Spanish Ministry of Science and Innovation, grant to established research groups (AECC) and grant S2011/BMD-2344/Colomics2 from Comunidad de Madrid. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Project
Comunidad de Madrid. S2010/BMD-2344/COLOMICS2; Gobierno de España. BIO2009-08818Editor's Version
http://dx.doi.org/10.1371/journal.pone.0063695Subjects
Colorectal cancer; Complement receptors; Fibroblast; Growth factors; Inmune receptor signaling; Inmune receptors; Mutation; SW480 cells; Biología y Biomedicina / BiologíaAbstract
Fibroblast growth factor receptor 4 (FGFR4) is vital in early development and tissue repair. FGFR4 expression levels are very
restricted in adult tissues, except in several solid tumors including colorectal cancer, which showed overexpression of
FGFR4. Here, FGFR4 mutation analysis discarded the presence of activating mutations, other than Arg388, in different
colorectal cancer cell lines and tumoral samples. Stable shRNA FGFR4-silencing in SW480 and SW48 cell lines resulted in a
significant decrease in cell proliferation, adhesion, cell migration and invasion. This decrease in the tumorigenic and invasive
capabilities of colorectal cancer cells was accompanied by a decrease of Snail, Twist and TGFb gene expression levels and an
increase of E-cadherin, causing a reversion to a more epithelial phenotype, in three different cell lines. In addition, FGFR4-
signaling activated the oncogenic SRC, ERK1/2 and AKT pathways in colon cancer cells and promoted an increase in cell
survival. The relevance of FGFR4 in tumor growth was supported by two different strategies. Kinase inhibitors abrogated
FGFR4-related cell growth and signaling pathways at the same extent than FGFR4-silenced cells. Specific FGFR4-targeting
using antibodies provoked a similar reduction in cell growth. Moreover, FGFR4 knock-down cells displayed a reduced
capacity for in vivo tumor formation and angiogenesis in nude mice. Collectively, our data support a crucial role for FGFR4 in
tumorigenesis, invasion and survival in colorectal cancer. In addition, FGFR4 targeting demonstrated its applicability for
colorectal cancer therapy.
Files in this item
Google Scholar:Peláez-García, Alberto
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Barderas, Rodrigo
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Torres, Sofía
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Hernández-Varas, Pablo
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Teixidó, Joaquín
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Bonilla, Félix
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García de Herreros, Antonio
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Casal, J. Ignacio
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