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

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

Research output: Contribution to journalArticle

113 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4095-4105
Number of pages11
JournalJournal of Clinical Investigation
Volume121
Issue number10
DOIs
StatePublished - Oct 3 2011

ASJC Scopus subject areas

  • Medicine(all)

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