TRAF6 is an amplified oncogene bridging the RAS and NF-κB pathways in human lung cancer
Daniel T. Starczynowski, … , Wan L. Lam, Aly Karsan
Daniel T. Starczynowski, … , Wan L. Lam, Aly Karsan
Published September 12, 2011
Citation Information: J Clin Invest. 2011;121(10):4095-4105. https://doi.org/10.1172/JCI58818.
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Research Article Oncology

TRAF6 is an amplified oncogene bridging the RAS and NF-κB pathways in human lung cancer

Abstract

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-κB 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-κB 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-κB activation in RAS-driven lung cancers.

Authors

Daniel T. Starczynowski, William W. Lockwood, Sophie Deléhouzée, Raj Chari, Joanna Wegrzyn, Megan Fuller, Ming-Sound Tsao, Stephen Lam, Adi F. Gazdar, Wan L. Lam, Aly Karsan

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Figure 1

TRAF6 locus amplification occurs frequently in lung cancer.

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TRAF6 locus amplification occurs frequently in lung cancer. (A) Cop...
(A) Copy number data for 85 lung cancer lines is shown by genomic location (rows). False discovery rates (q values; 0.25 cutoff for significance shown by green line) and scores for amplicons are plotted at each genome position. Individual chromosomes are denoted by white and gray shading; black boxes indicate significant high-level amplifications. (B) Copy number status of chromosome 11p for 2 representative lung cancer lines. The minimally amplified region spanning chromosome 11p13 to 11p12 (32,126,542–37,251,933) and known genes are shown at right. Normalized log2 signal intensity ratios were plotted and visualized by SIGMA2 (32). Vertical lines denote log2 signal ratios from –1 to +1; copy number gains (red) are to the right of 0. Each dot represents a single probe. (C) A subset of 66 lung cancer samples was analyzed to identify genes whose expression correlated with gene amplification. P values (–log2) for genes within the minimally amplified region on 11p13 are shown as a histogram. Values above the dashed line denote P ≤ 0.05. (D) IB for TRAF6 and actin in 5 lung cancer lines diploid at 11p13 (N, no 11p13 amplification; H2171, H1395, H2347, H520, and H460) and 4 lung cancer lines with an 11p13 amplification (amp; HCC95, H526, H2171, and SK-MES-1). Densitometric values for TRAF6 protein relative to actin are shown below. (E) TRAF6 mRNA levels were evaluated in lung tumor samples with (n = 13) and without (n = 31) amplification of 11p13. Significance was determined by Mann-Whitney U test. *P < 0.05.