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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

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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 3

Inhibition of TRAF6 impairs growth and tumor formation of lung cancer cells.

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Inhibition of TRAF6 impairs growth and tumor formation of lung cancer ce...
(A) Growth curves of cell lines with TRAF6 inhibition (shT6) is shown relative to vector-expressing (pLKO.1 control) cells. (B and C) Soft agar colony formation for the indicated cell lines after TRAF6 inhibition. Original magnification, ×20. (D) Cell lines H460 and HCC95 were transduced with virus encoding shT6. After TRAF6 inhibition, cell survival was evaluated by flow cytometry for Annexin V expression. HCC95 cells transduced with vector or shT6 were also cultured in liquid media, and morphological assessment confirmed that shT6-expressing cells exhibited features of increased cell death, such as cell detachment and shrinkage and membrane blebbing. Original magnification, ×40. (E–G) Cell lines H1395 (E), H460 (F), and HCC95 (G), transduced with vector (pLKO.1-control) or shT6, were subcutaneously injected into NOD/SCID mice. Tumor volume is shown at the experimental endpoint. *P < 0.05.

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