Overexpression of fibroblast growth factor receptor 4 in high-grade pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma

Abstract

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.