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

J Clin Invest. 2011 Oct;121(10):4095-105. doi: 10.1172/JCI58818. Epub 2011 Sep 12.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Non-Small-Cell Lung / etiology
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Small Cell / etiology
  • Carcinoma, Small Cell / genetics
  • Carcinoma, Small Cell / metabolism
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Chromosomes, Human, Pair 11 / genetics
  • Gene Amplification
  • Humans
  • Lung Neoplasms / etiology
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • NF-kappa B / metabolism*
  • NIH 3T3 Cells
  • Oncogenes
  • Signal Transduction
  • TNF Receptor-Associated Factor 6 / deficiency
  • TNF Receptor-Associated Factor 6 / genetics*
  • Tumor Stem Cell Assay
  • ras Proteins / metabolism*

Substances

  • NF-kappa B
  • TNF Receptor-Associated Factor 6
  • ras Proteins