Inhibition of fibroblast growth factor receptor 2 attenuates proliferation and invasion of pancreatic cancer.
Inhibition of fibroblast growth factor receptor 2 attenuates proliferation and invasion of pancreatic cancer.
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DOI：
10.1111/cas.12470
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发表时间：
2014-09
期刊：
影响因子：
5.7
通讯作者：
Ishiwata T
中科院分区：
文献类型：
--
作者：
Matsuda Y;Yoshimura H;Suzuki T;Uchida E;Naito Z;Ishiwata T
成纤维细胞生长因子受体（FGFR）-2的细胞外结构域的选择性剪接产生IIIb和IIIc同种型。FGFR-2 IIIb的表达与血管内皮生长因子-A（VEGF-A）表达和胰腺导管腺癌（PDAC）的静脉浸润相关。相比之下，FGFR-2 IIIc表达与手术后肝转移的更快发展以及癌症的增殖率和侵袭性增加相关。在这项研究中，我们分析了总FGFR-2（两种亚型）的表达和作用，以确定FGFR-2靶向治疗PDAC的有效性。免疫组化结果显示，FGFR-2在48例PDAC中有25例（52.1%）高表达，且与晚期癌症相关。在FISH分析中，FGFR 2在3/7个PDAC细胞系中扩增。我们将靶向IIIb和IIIc亚型的FGFR-2 shRNA稳定转染到FGFR 2扩增的PDAC细胞中。转染FGFR-2-shRNA的细胞在体外的增殖率、迁移率和侵袭力均低于对照细胞。与对照细胞相比，FGFR-2-shRNA转染细胞对FGF-2的反应显示ERK磷酸化降低。转染FGFR-2-shRNA的细胞表达的血管内皮生长因子-A水平也低于对照细胞，并形成较小的s.c.裸鼠肿瘤。这些发现表明FGFR-2是PDAC中抑制的治疗靶标。
The alternative splicing of the extracellular domain of fibroblast growth factor receptor (FGFR)-2 generates the IIIb and IIIc isoforms. Expression of FGFR-2 IIIb correlates with vascular endothelial growth factor-A (VEGF-A) expression and venous invasion of pancreatic ductal adenocarcinoma (PDAC). By contrast, FGFR-2 IIIc expression correlates with faster development of liver metastasis after surgery, and increased proliferation rates and invasion of the cancer. In this study, we analyzed the expression and roles of total FGFR-2 (both isoforms) to determine the effectiveness of FGFR-2-targeting therapy for PDAC. Immunohistochemically, FGFR-2 was highly expressed in 25/48 (52.1%) PDAC cases, and correlated with advanced stage cancer. In FISH analysis, FGFR2 was amplified in 3/7 PDAC cell lines. We stably transfected an FGFR-2 shRNA targeting the IIIb and IIIc isoforms into FGFR2-amplified PDAC cells. The proliferation rates, migration, and invasion of FGFR-2-shRNA-transfected cells were lower than those of control cells in vitro. In response to FGF-2, FGFR-2-shRNA-transfected cells showed decreased phosphorylation of ERK compared with control cells. The FGFR-2-shRNA-transfected cells also expressed lower levels of vascular endothelial growth factor-A than control cells, and formed smaller s.c. tumors in nude mice. These findings suggest that FGFR-2 is a therapeutic target for inhibition in PDAC.
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影响因子：
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