TRAF4 overexpression is a common characteristic of human carcinomas

Abstract

Tumor necrosis factor receptor (TNFR) associated factor 4 (TRAF4) was initially identified as a gene amplified and overexpressed in breast carcinomas. Our aim was to evaluate whether TRAF4 protein overexpression exists in other cancer types. Immunohistochemistry analysis of tumor samples from 623 patients with 20 different tumor types showed that TRAF4 was overexpressed in 268 tumors (43%), including 82 of 137 lung adenocarcinomas (60%). Interestingly, 32 primary tumors and their matching metastases exhibited mostly similar TRAF4 expression pattern. TRAF4 protein overexpression was limited to cancer cells and the subcellular localization was consistently cytoplasmic in a large majority of cases. To investigate changes in TRAF4 gene copy number, 125 cases from six different types of carcinomas were also analysed by fluorescence in situ hybridization. Out of the 28 cases (22%) showing an increased TRAF4 gene copy number, 23 (82%) were overexpressing the protein. Thus, TRAF4 gene amplification is one of the mechanisms responsible for TRAF4 protein overexpression in human cancers. Considering that TRAF4 is located at 17q11.2 in a region of amplification devoid of known oncogenes and is commonly overexpressed in cancer, our data support an oncogenic role for TRAF4. Oncogene Keywords: TRAF4; chromosome 17q11; ERBB2; amplification; lung TRAF proteins belong to a family of cytoplasmic adaptors involved in the signalling cascade activated by receptors of the TNFR and interleukin-1/Toll-like receptor (IL-1R/TLR) families (Chung et al., 2002). Six TRAF proteins that share common structural features, including a carboxy-terminal TRAF domain, are encoded by the mammalian genome. Their main functions are exerted in the immune system where they regulate intracellular signalling pathways leading to the activation of a common set of transcription factors including NF-kB and AP-1 (Aggarwal, 2003).Unlike other members of the TRAF family, the biological function of TRAF4 remains elusive. Several reports suggested that TRAF4 could be recruited to different TNFR and TLR signalling pathways (Krajewska et al., 1998;Ye et al., 1999;Esparza and Arch, 2004;Takeshita et al., 2005), and in mitogen-activated protein kinase (MAPK) pathways (Xu et al., 2002;Abell and Johnson, 2005;Li et al., 2005) but in vivo evidence of such a role is still missing. Mice deficient for TRAF4 exhibit clear ontogenic defects affecting neural tube closure, tracheal formation and skeletal patterning, phenotypes that might be linked to abnormal cell migration (Regnier et al., 2002).TRAF4 was the first member of the TRAF protein family found upregulated in human carcinomas. Indeed, the TRAF4 cDNA was initially isolated from metastatic breast cancer Tomasetto et al., 1995), where the TRAF4 gene was amplified, leading to overexpression of the gene product (Bieche et al., 1996). Detailed analysis of the amplification pattern of five genes located on the long arm of the chromosome 17, including the ERBB2 oncogene (Slamon et al., 1989), revealed the existence of at least...

The phosphoinositide-binding protein TRAF4 modulates tight junction stability and migration of cancer cells

“…16 Interestingly, in mammary cancer cells, TRAF4 localization is altered: while it is still present in TJs in well differentiated tumors, the protein is relocalized in the cytoplasm and the nucleus in poorly differentiated tumors, indicating that TRAF4 functions differently in cancer cells. 8,9,16,20 TRAF4 is a typical TRAF protein composed of 3 distinct modular domains, an N-terminal RING domain, a succession of 7 zinc fingers (ZF), and a C-terminal TRAF domain. 15 The RING domain of TRAF4 was shown to confer an E3-ligase activity to the protein, the 7 central ZF have an unknown function but, by analogy with other TRAF proteins, are most probably involved in protein-protein interactions, and the TRAF domain governs the trimerization of the protein.…”

“…[8][9][10][11]12 TRAF4 belongs to the TRAF family which is composed of 7 members in human. 13,14 Unlike the other TRAF proteins, which function predominantly in inflammation and immunity, TRAF4 is mainly involved in developmental and morphogenetic processes.…”

TRAF4 is potently induced by TAp63 isoforms and localised according to differentiation in SCCHN

“…Similarly, the previous study found some tumors to contain only nuclear TRAF4, although in that study most contained cytoplasmic staining and no link was made with differential localization and tumor differentiation. 25 These data imply that localization of TRAF4 is regulated differently in different tumors and that localization may influence differentiation processes of malignant squamous epithelial cells. The differential localization of TRAF4 and any consequent functional effects are tumor-specific events, since we did not observe cytoplasmic staining in normal tissue.…”

“…High level expression of TRAF4 was associated with amplification of the TRAF4 gene locus in a minority of the TRAF4-positive tumors, 25 implying that other regulatory factors lead to increased TRAF4 expression in some tumors. We found that TRAF4 is easily detectable using immunohistochemistry on primary human SCCHN.…”

“…21,22 Originally identified as a protein localized in the nucleus of breast carcinoma cells, 23 TRAF4 has also been reported as a cytosolic protein. 21,24 TRAF4 is commonly over-expressed in human carcinomas with both nuclear and cytoplasmic localizations, 25 although the significance of expression and differential subcellular location remains unknown.…”