title: 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.affiliation: British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Starczynowski
authors.forename: William W
authors.initials: WW
authors.lastname: Lockwood
authors.forename: Sophie
authors.initials: S
authors.lastname: Deléhouzée
authors.forename: Raj
authors.initials: R
authors.lastname: Chari
authors.forename: Joanna
authors.initials: J
authors.lastname: Wegrzyn
authors.forename: Megan
authors.initials: M
authors.lastname: Fuller
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
authors.forename: Stephen
authors.initials: S
authors.lastname: Lam
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
authors.forename: Wan L
authors.initials: WL
authors.lastname: Lam
authors.forename: Aly
authors.initials: A
authors.lastname: Karsan
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D018288:Carcinoma, Small Cell / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D005784:Gene Amplification; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009857:Oncogenes; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000172:deficiency / Q000235:genetics*; D014410:Tumor Stem Cell Assay; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D018631:ras Proteins