Department of Pathology, Integrative Oncological Pathology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
Int J Oncol. 2011 Jan;38(1):133-43.
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.
成纤维细胞生长因子受体 4（FGFR4）的过表达已在各种人类癌症中报道，但在胰腺导管腺癌（PDAC）或其前体病变胰腺上皮内瘤变（PanIN）中尚未研究。此外，FGFR4 在致癌作用中是否具有促有丝分裂作用或其他功能存在争议。因此，研究了 FGFR4 在胰腺癌中的表达和作用。使用抗 FGFR4 抗体对 PDAC 和 PanIN 病例进行免疫组织化学染色。通过 qRT-PCR 和 Western blot 分别研究 PDAC 细胞系中 FGFR4 mRNA 和蛋白的表达水平。用 FGF19 刺激 PDAC 细胞系，分析 FGFR4 刺激后细胞形态、增殖、迁移、侵袭和附着的变化，FGF19 是一种已知的特异性配体。还评估了 FGF19 给药导致的与转化和肿瘤发生相关的 mRNA 水平的变化。FGFR4 在 53 例 PDAC 病例中的 39 例（73.6%）中表达，其表达倾向于与总体生存时间延长相关（P=0.068）。此外，它在高级别 PanIN 病变中频繁表达[11 例病变中的 10 例（90.9%）]，而在低级别 PanIN 病变中几乎不表达[10 例病变中的 1 例（10.0%）]（P=0.0003）。PDAC 细胞中 FGFR4 的刺激导致细胞对层粘连蛋白和纤维连接蛋白的粘附显著增加（P<0.05），细胞迁移减少（P<0.05）。PCR 阵列分析的结果表明，这是整联蛋白 α4 家族上调的结果。相比之下，PDAC 细胞的细胞形态或增殖不受影响。我们表明，与正常和低级别 PanIN 相比，FGFR4 在高级别 PanIN 和 PDAC 中的表达明显增加，并且 PDAC 细胞中 FGF19 对 FGFR4 的刺激通过增加细胞对细胞外基质的粘附来促进肿瘤抑制。
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