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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 4

TRAF6 is upstream of NF-κB in human lung cancer cells.

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TRAF6 is upstream of NF-κB in human lung cancer cells.
(A) NF-κB activit...
(A) NF-κB activity was measured by κB-site luciferase assays in human lung cancer cells with (HCC95, H526, H2171, HTB58) and without (H2170, H2347, H520, HTB117) amplification of the TRAF6 locus (11p13). (B) Nuclear NF-κB (p65) was IB in nuclear extracts from 7 human lung cancer cell lines with (H2170, H2347, H520) or without (H2170, H2347, H520, HTB117) amplification at the TRAF6 locus (11p13). (C) H460 (diploid at 11p13) and HCC95 (amplification of 11p13) were evaluated for κB-site luciferase activity and for TRAF6 protein expression. (D) NF-κB activity was measured by κB-site luciferase assays after TRAF6 inhibition. *P < 0.05.

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