The overexpression of
fibroblast growth factor receptor (FGFR) 4 has been reported in various human
cancers, but it has not been studied in pancreatic ductal
adenocarcinoma (PDAC) or its precursor lesion, pancreatic intraepithelial
neoplasia (PanIN). Moreover, there is controversy as to whether FGFR4 has a mitogenic role in
carcinogenesis or other functions. Therefore, the expression and roles of FGFR4 in
pancreatic cancer were investigated. Immunohistochemical staining was performed using an anti-FGFR4 antibody in PDAC and PanIN cases. The expression levels of FGFR4
mRNA and
protein were investigated in PDAC cell lines by qRT-PCR and Western blot, respectively. Changes were analyzed in cell morphology, proliferation, migration, invasion and attachment in PDAC cell lines with or without the stimulation of FGFR4 by FGF19, as a known specific
ligand. The changes in
mRNA levels associated with transformation and
tumorigenesis as a result of FGF19 administration were also evaluated. FGFR4 was expressed in 39 of 53 PDAC cases (73.6%) and its expression tended to be related to longer overall survival (P=0.068). Moreover, it was frequently expressed in high-grade PanIN lesions [10 of 11 lesions (90.9%)], whereas it was hardly expressed in low-grade PanIN lesions [1 of 10 lesions (10.0%)] (P=0.0003). FGFR4 stimulation of PDAC cells resulted in significantly increased cell adhesion to
laminin and
fibronectin (P<0.05) and decreased cell migration (P<0.05). The results of PCR array analysis indicated that this was a result of up-regulation of the
integrin α4 family. In contrast, cell morphology or proliferation in PDAC cells was not affected. We showed that FGFR4 expression is markedly increased in high-grade PanIN and PDAC compared with that in normal and low-grade PanIN, and that FGFR4 stimulation by FGF19 of PDAC cells contributes to
tumor suppression by increasing cell adhesion to extracellular matrix.