Fibroblast growth factor receptor 2 expression, but not its genetic amplification, is associated with tumor growth and worse survival in esophagogastric junction adenocarcinoma.
Fibroblast growth factor receptor 2 expression, but not its genetic amplification, is associated with tumor growth and worse survival in esophagogastric junction adenocarcinoma.
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DOI：
10.18632/oncotarget.7782
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发表时间：
2016-04-12
期刊：
影响因子：
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通讯作者：
Baba H
中科院分区：
文献类型：
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作者：
Tokunaga R;Imamura Y;Nakamura K;Ishimoto T;Nakagawa S;Miyake K;Nakaji Y;Tsuda Y;Iwatsuki M;Baba Y;Sakamoto Y;Miyamoto Y;Saeki H;Yoshida N;Oki E;Watanabe M;Oda Y;Bass AJ;Maehara Y;Baba H
成纤维细胞生长因子受体2（FGFR2）基因改变导致各种类型癌症中的肿瘤细胞增殖。我们假设FGFR2扩增与FGFR2表达相关，导致食管胃连接部（EGJ）腺癌的肿瘤生长和不良结局。从两个学术机构共入组了176例连续的EGJ腺癌化疗初治患者。通过实时PCR检测FGFR2扩增（N = 140），通过免疫组织化学染色检测FGFR2表达（N = 176），并与临床病理因素和患者结局进行比较。在EGJ腺癌细胞系中研究了FGFR 2抑制或过表达对细胞增殖、细胞周期和凋亡测定的影响。还检测了下游FGFR 2、AKT和ERK。基于体外FGFR 2水平与FGFR 2过表达之间的相关性，FGFR 2扩增定义为拷贝数> 3.0。在临床样本中，FGFR 2扩增和FGFR 2 IHC表达分别为15%和61%。尽管这两种状态显著相关（P < 0.05），但只有FGFR 2 IHC表达与肿瘤深度（多变量P < 0.001）和患者总生存期（单变量P = 0.007）显著相关。支持这些发现，FGFR2过表达与肿瘤细胞增殖，细胞周期进展和抗凋亡相关。选择性抑制FGFR2通过AKT和ERK的去磷酸化充分抑制肿瘤细胞增殖。FGFR2扩增与FGFR2表达显著相关。FGFR2表达（而非FGFR2扩增）与肿瘤生长和患者结局相关。我们的研究结果支持FGFR2作为EGJ腺癌的新治疗靶点。
Fibroblast growth factor receptor 2 (FGFR2) genetic alterations lead to tumor cell proliferation in various types of cancer. We hypothesized that FGFR2 amplification is associated with FGFR2 expression, resulting in tumor growth and poorer outcome in esophagogastric junction (EGJ) adenocarcinoma. A total of 176 consecutive chemo-naive patients with EGJ adenocarcinoma were enrolled from two academic institutions. FGFR2 amplification was examined by real-time PCR (N = 140) and FGFR2 expression with immunohistochemical staining (N = 176), and compared against clinicopathological factors and patient outcomes. The effects of FGFR2 inhibition or overexpression on cell proliferation, cell cycle, and apoptosis assays were investigated in EGJ adenocarcinoma cell lines. Downstream FGFR2, AKT and ERK were also examined. Based on the correlation between FGFR2 levels and FGFR2 overexpression in vitro, FGFR2 amplification was defined as copy number > 3.0. In clinical samples, FGFR2 amplification and FGFR2 IHC expression were 15% and 61%, respectively. Although these two statuses were significantly correlated (P < 0.05), only FGFR2 IHC expression was significantly associated with tumor depth (multivariate P < 0.001) and overall survival of patients (univariate P = 0.007). Supporting these findings, FGFR2 overexpression was associated with tumor cell proliferation, cell cycle progression, and anti-apoptosis. Selective inhibition of FGFR2 sufficiently suppressed tumor cell proliferation through de-phosphorylation of AKT and ERK. FGFR2 amplification was significantly associated with FGFR2 expression. FGFR2 expression (but not FGFR2 amplification) was associated with tumor growth and patient outcomes. Our findings support FGFR2 as a novel therapeutic target for EGJ adenocarcinoma.