Fibroblast growth factor receptor 1 oncogene partner as a novel prognostic biomarker and therapeutic target for lung cancer
Fibroblast growth factor receptor 1 oncogene partner as a novel prognostic biomarker and therapeutic target for lung cancer
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DOI：
10.1111/j.1349-7006.2007.00610.x
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发表时间：
2007-12-01
期刊：
影响因子：
5.7
通讯作者：
Daigo, Yataro
中科院分区：
文献类型：
--
作者：
Mano, Yuria;Takahashi, Koji;Daigo, Yataro
为了筛选可能用作诊断生物标志物或用于开发新型分子靶向疗法的候选分子，我们先前对101例肺癌进行了基因表达谱分析，并检测到成纤维细胞生长因子受体1癌基因伴侣（FGFR1OP）在大多数肺癌中表达升高。利用由372份存档的非小细胞肺癌（NSCLC）标本组成的肿瘤组织微阵列进行免疫组化染色，结果显示372例NSCLC中有334例（89.8%）FGFR1OP呈阳性染色。我们还发现FGFR1OP的高表达水平与较短的肿瘤特异性生存时间显著相关（通过对数秩检验，P < 0.0001）。此外，多变量分析确定FGFR1OP是手术治疗的NSCLC患者的一个独立预后因素（P < 0.0001）。使用FGFR1OP小干扰RNA处理内源性FGFR1OP过表达的肺癌细胞，可抑制其表达并导致细胞生长受抑。此外，FGFR1OP的诱导增加了哺乳动物细胞的细胞运动性和促生长活性。为了研究其功能，我们在肺癌细胞中寻找与FGFR1OP相互作用的蛋白质，并鉴定出ABL1（艾贝尔森鼠白血病病毒癌基因同源物1）和WRNIP1（沃纳解旋酶相互作用蛋白1），已知它们参与细胞周期进程。FGFR1OP显著降低了WRNIP1的ABL1依赖性磷酸化，并导致细胞周期进程的促进。由于我们的数据表明FGFR1OP可能在肺癌生长和进展中起重要作用，因此FGFR1OP应可用作预后生物标志物，并且可能作为肺癌的治疗靶点。
To screen candidate molecules that might be useful as diagnostic biomarkers or for development of novel molecular-targeting therapies, we previously carried out gene-expression profile analysis of 101 lung carcinomas and detected an elevated expression of FGFR1OP (fibroblast growth factor receptor 1 oncogene partner) in the majority of lung cancers. Immunohistochemical staining using tumor tissue microarrays consisting of 372 archived non-small cell lung cancer (NSCLC) specimens revealed positive staining of FGFR1OP in 334 (89.8%) of 372 NSCLCs. We also found that the high level of FGFR1OP expression was significantly associated with shorter tumor-specific survival times (P < 0.0001 by log-rank test). Moreover, multivariate analysis determined that FGFR1OP was an independent prognostic factor for surgically treated NSCLC patients (P < 0.0001). Treatment of lung cancer cells, in which endogenous FGFR1OP was overexpressed, using FGFR1OP siRNA, suppressed its expression and resulted in inhibition of the cell growth. Furthermore, induction of FGFR1OP increased the cellular motility and growth-promoting activity of mammalian cells. To investigate its function, we searched for FGFR1OP-interacting proteins in lung cancer cells and identified ABL1 (Abelson murine leukemia viral oncogene homolog 1) and WRNIP1 (Werner helicase interacting protein 1), which was known to be involved in cell cycle progression. FGFR1OP significantly reduced ABL1-dependent phosphorylation of WRNIP1 and resulted in the promotion of cell cycle progression. Because our data imply that FGFR1OP is likely to play a significant role in lung cancer growth and progression, FGFR1OP should be useful as a prognostic biomarker and probably as a therapeutic target for lung cancer.