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.

Expression of Tumor Necrosis Factor Receptor-associated Factor 6 in Lung Cancer Tissues

“…We also assessed the diagnostic significance of TRAF6 protein by a ROC curve and found that TRAF6 protein has a moderate diagnostic value in lung cancer (AUC=0.663). In line with our results, Starczynowsk's (Starczynowski et al, 2011) reported that TRAF6 mRNA and protein expression were both highly expressed in 85 lung cancer cell lines. Additionally, TRAF6 protein was positively correlated with enhanced colony formation in NIH3T3 Cells.…”

“…Additionally, TRAF6 protein was positively correlated with enhanced colony formation in NIH3T3 Cells. Starczynowski's (Starczynowski et al, 2011) also observed that TRAF6 overexpression resulted in malignant transformation of fibroblasts and tumor formation, whereas knockdown of TRAF6 suppressed human lung cancer growth and RAS-mediated tumor formation. Together with the report of Starczynowski's (Starczynowski et al, 2011), our current results support that TRAF6 might be an oncogene for lung cancer, playing a similar role as in other malignancies, such as breast cancer, leukemia and esophageal adenocarcinoma (Beroukhim et al, 2010), colon cancer (Sun et al, 2014) and osteosarcoma (Meng et al, 2012).…”

“…The levels of TRAF6 expression, including its mRNA and protein, were validated in vitro of lung cancer (Starczynowski et al, 2011;Zhong et al, 2013). However, only mRNA of TRAF6 was detected in clinical patient samples (Starczynowski et al, 2011). Therefore, in the current study, we focused on the expression of TRAF6 protein and its association with clinicopathological parameters in lung cancer patients…”

“…However, the role and mechanism of TRAF6 in lung cancer have not been extensively investigated. The levels of TRAF6 expression, including its mRNA and protein, were validated in vitro of lung cancer (Starczynowski et al, 2011;Zhong et al, 2013). However, only mRNA of TRAF6 was detected in clinical patient samples (Starczynowski et al, 2011).…”

Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma

“…[25][26][27] TRAF6, initially identified as a regulator of NF-κB, also has an important role in tumorigenesis, invasion and metastasis, by modulating various signaling pathways. [28][29][30] Finally, because SASH1 has recently been reported as a scaffold molecule implicated in endothelial TLR4 signaling, which is implicated in innate immune responses, we wondered whether palmoplantar keratoderma and alopecia could be due to chronic fungal infection, but this hypothesis was ruled out. 25 Dermatological diseases provide key examples of diseases with variants in the same gene that can either follow autosomaldominant or -recessive inheritance.…”