TRAF6 is an amplified oncogene bridging the RAS and NF-κB pathways in human lung cancer
TRAF6 is an amplified oncogene bridging the RAS and NF-κB pathways in human lung cancer
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DOI：
10.1172/jci58818
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发表时间：
2011-10-01
影响因子：
15.9
通讯作者：
Karsan, Aly
中科院分区：
文献类型：
--
作者：
Starczynowski, Daniel T.;Lockwood, William W.;Karsan, Aly
体细胞突变和拷贝数改变(由于染色体的大部分缺失或扩增)是人类肺癌的主要驱动因素。对肺癌相关染色体扩增的详细分析可以识别新的癌基因。通过对非小细胞肺癌(NSCLC)和小细胞肺癌(SCLC)细胞系和肿瘤进行细胞遗传学和基因表达的综合分析，我们在这里报告了染色体11带p13的一个频繁重复的扩增。在该区域内，只有肿瘤坏死因子受体相关因子6(TRAF6)在肺癌中表现出伴随的mRNA过度表达和基因扩增。抑制人肺癌细胞系中的TRAF6可抑制核因子-kappaB的激活、锚定非依赖性生长和肿瘤形成。在这些肺癌细胞系中，RAS要求TRAF6具有致癌能力。此外，TRAF6在NIH3T3细胞中的过表达导致了NF-kappa B的激活、非锚定生长和肿瘤的形成。我们的发现表明，TRAF6是一个癌基因，在RAS介导的肿瘤发生中是重要的，并为以前在RAS驱动的肺癌中结构性的NF-kappa B激活的重要性提供了一个机制解释。
Somatic mutations and copy number alterations (as a result of deletion or amplification of large portions of a chromosome) are major drivers of human lung cancers. Detailed analysis of lung cancer-associated chromosomal amplifications could identify novel oncogenes. By performing an integrative cytogenetic and gene expression analysis of non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) cell lines and tumors, we report here the identification of a frequently recurring amplification at chromosome 11 band p13. Within this region, only TNF receptor-associated factor 6 (TRAF6) exhibited concomitant mRNA overexpression and gene amplification in lung cancers. Inhibition of TRAF6 in human lung cancer cell lines suppressed NF-kappa B activation, anchorage-independent growth, and tumor formation. In these lung cancer cell lines, RAS required TRAF6 for its oncogenic capabilities. Furthermore, TRAF6 overexpression in NIH3T3 cells resulted in NF-kappa B activation, anchorage-independent growth, and tumor formation. Our findings show that TRAF6 is an oncogene that is important for RAS-mediated oncogenesis and provide a mechanistic explanation for the previously apparent importance of constitutive NF-kappa B activation in RAS-driven lung cancers.