Abstract
The tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family of cytoplasmic adaptor proteins regulate the signal transduction pathways of a variety of receptors, including the TNF-R superfamily, Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), and cytokine receptors. TRAF-dependent signaling pathways participate in a diverse array of important cellular processes, including the survival, proliferation, differentiation, and activation of different cell types. Many of these TRAF-dependent signaling pathways have been implicated in cancer pathogenesis. Here we analyze the current evidence of genetic alterations of TRAF molecules available from The Cancer Genome Atlas (TCGA) and the Catalog of Somatic Mutations in Cancer (COSMIC) as well as the published literature, including copy number variations and mutation landscape of TRAFs in various human cancers. Such analyses reveal that both gain- and loss-of-function genetic alterations of different TRAF proteins are commonly present in a number of human cancers. These include pancreatic cancer, meningioma, breast cancer, prostate cancer, lung cancer, liver cancer, head and neck cancer, stomach cancer, colon cancer, bladder cancer, uterine cancer, melanoma, sarcoma, and B cell malignancies, among others. Furthermore, we summarize the key in vivo and in vitro evidence that demonstrates the causal roles of genetic alterations of TRAF proteins in tumorigenesis within different cell types and organs. Taken together, the information presented in this review provides a rationale for the development of therapeutic strategies to manipulate TRAF proteins or TRAF-dependent signaling pathways in different human cancers by precision medicine.
Highlights
The tumor necrosis factor receptor (TNF-R)-associated factor (TRAF 1–7) family of cytoplasmic adaptor proteins regulates the signal transduction pathways of a variety of receptors, including the TNF-R superfamily, Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), and cytokine receptors [1,2,3,4]
Similar to TRAF2 and consistent with the frequent deletions and inactivating mutations of TRAF3 identified in human B cell malignancies (Figure 1B), a tumor suppressive role for TRAF3 in B lymphocytes has been demonstrated by in vivo evidence obtained from mouse models
We have analyzed the current evidence of genetic alterations of the TRAF family in human cancers
Summary
The tumor necrosis factor receptor (TNF-R)-associated factor (TRAF 1–7) family of cytoplasmic adaptor proteins regulates the signal transduction pathways of a variety of receptors, including the TNF-R superfamily, Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), and cytokine receptors [1,2,3,4]. Genetic alterations of TRAF2 are detected in 1–2% of human liver cancers, including deletion, mutation and amplification (TCGA, PanCancer Atlas) [119]. A variety of TRAF2-dependent oncogenic pathways have been reported based on studies of patient samples, cultured human cancer cells or xenograft models.
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