Up-regulation of 14-3-3ζ in lung cancer and its implication as prognostic and therapeutic target
Up-regulation of 14-3-3ζ in lung cancer and its implication as prognostic and therapeutic target
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DOI：
10.1158/0008-5472.can-07-0090
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发表时间：
2007-08-15
期刊：
影响因子：
11.2
通讯作者：
Jiang, Feng
中科院分区：
文献类型：
--
作者：
Fan, Tao;Li, Ruiyun;Jiang, Feng
结合基因芯片和蛋白质组分析的功能基因组学方法已经确定14-3-3 Zeta是一个可能的癌基因，它的激活在肺腺癌中很常见，并且是由其基因组扩增驱动的。14-3-3Zeta被认为在细胞信号、周期控制和凋亡死亡中发挥作用。根据我们的初步发现，在这里，我们用免疫组织化学方法分析了205例不同组织学和分期的非小细胞肺癌(NSCLC)患者肺肿瘤组织中该基因的表达，然后利用小干扰RNA在体外和异种移植模型中探讨了特异性抑制该基因的效果。14-3-3Zeta的表达与NSCLC的病理分期和分级呈正相关(P=0.001和P=0.006)，与患者的总体生存率和肿瘤特异性生存率呈正相关(P=0.022和P=0.018)。肺癌细胞14-3-3 Zeta表达下调，对顺铂诱导的细胞死亡的敏感性呈剂量依赖性增加，其机制与抑制细胞增殖、增加G(2)-M期细胞停滞和细胞凋亡有关。动物模型进一步证实了这一结果，发现顺铂处理后，14-3-3 Zeta降低的A549肺癌细胞生长速度明显慢于野生型A549细胞(P=0.008)。我们的结果表明，14-3-3 Zeta是一个潜在的靶点，可以开发一种预后生物标志物和治疗药物，以增强顺铂对非小细胞肺癌的抗肿瘤活性。
A functional genomic approach integrating microarray and proteomic analyses done in our laboratory has identified 14-3-3 zeta as a putative oncogene whose activation was common and driven by its genomic amplification in lung adenocarcinomas. 14-3-3 zeta is believed to function in cell signaling, cycle control, and apoptotic death. Following our initial finding, here, we analyzed its expression in lung tumor tissues obtained from 205 patients with various histologic and stage non-small cell lung cancers (NSCLC) using immunohistochemistry and then explored the effects of specific suppression of the gene in vitro and in a xenograft model using small interfering RNA. The increased 14-3-3 zeta expression was positively correlated with a more advanced pathologic stage and grade of NSCLCs (P = 0.001 and P = 0.006, respectively) and was associated with overall and cancer-specific survival rates of the patients (P = 0.022 and P = 0.018, respectively). Down-regulation of 14-3-3 zeta in lung cancer cells led to a dose-dependent increased sensitivity to cisplatin-induced cell death, which was associated with the inhibition of cell proliferation and increased G(2)-M arrest and apoptosis. The result was further confirmed in the animal model, which showed that the A549 lung cancer cells with reduced 14-3-3 zeta grew significantly slower than the wild-type A549 cells after cisplatin treatment (P = 0.008). Our results suggest that 14-3-3 zeta is a potential target for developing a prognostic biomarker and therapeutics that can enhance the antitumor activity of cisplatin for NSCLC.