Gene Summary

Gene:TRAF6; TNF receptor associated factor 6
Aliases: RNF85, MGC:3310
Summary:The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins are associated with, and mediate signal transduction from, members of the TNF receptor superfamily. This protein mediates signaling from members of the TNF receptor superfamily as well as the Toll/IL-1 family. Signals from receptors such as CD40, TNFSF11/RANCE and IL-1 have been shown to be mediated by this protein. This protein also interacts with various protein kinases including IRAK1/IRAK, SRC and PKCzeta, which provides a link between distinct signaling pathways. This protein functions as a signal transducer in the NF-kappaB pathway that activates IkappaB kinase (IKK) in response to proinflammatory cytokines. The interaction of this protein with UBE2N/UBC13, and UBE2V1/UEV1A, which are ubiquitin conjugating enzymes catalyzing the formation of polyubiquitin chains, has been found to be required for IKK activation by this protein. This protein also interacts with the transforming growth factor (TGF) beta receptor complex and is required for Smad-independent activation of the JNK and p38 kinases. This protein has an amino terminal RING domain which is followed by four zinc-finger motifs, a central coiled-coil region and a highly conserved carboxyl terminal domain, known as the TRAF-C domain. Two alternatively spliced transcript variants, encoding an identical protein, have been reported. [provided by RefSeq, Feb 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:TNF receptor-associated factor 6
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (77)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Mutation
  • Apoptosis
  • Cell Proliferation
  • Toll-Like Receptor 4
  • Interleukin-1 Receptor-Associated Kinases
  • Biomarkers, Tumor
  • Cell Movement
  • Breast Cancer
  • Neoplastic Cell Transformation
  • Knockout Mice
  • Prostate Cancer
  • Messenger RNA
  • Bladder Cancer
  • Case-Control Studies
  • Signal Transduction
  • Carcinogenesis
  • Chromosome 11
  • Neoplasm Proteins
  • RNA Interference
  • MicroRNAs
  • Oligonucleotide Array Sequence Analysis
  • Tongue Neoplasms
  • Gene Knockdown Techniques
  • ras Proteins
  • NF-kappa B
  • Transfection
  • Gene Expression Profiling
  • Single Nucleotide Polymorphism
  • Protein Binding
  • Up-Regulation
  • Cancer Gene Expression Regulation
  • Young Adult
  • siRNA
  • Phosphorylation
  • Neoplasm Invasiveness
  • HEK293 Cells
  • TNF Receptor-Associated Factor 6
  • Neoplasm Metastasis
  • Skin Cancer
  • Lung Cancer
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TRAF6 (cancer-related)

Li T, Li M, Xu C, et al.
miR‑146a regulates the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis through NF‑κB signaling by targeting TRAF6.
Oncol Rep. 2019; 41(5):2897-2908 [PubMed] Related Publications
The aim of the present study was to investigate whether miRNA‑146a regulated the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis. miR‑146a expression was increased in human cervical cancer. Both overall survival (OS) and disease‑free survival (DFS) of low miR‑146a expression were higher than those of high miR‑146a expression. Additionally, IL‑17a expression was lower in patients with high miR‑146a expression compared to that of patients with lower miR‑146a expression. In a co‑culture of cervical cancer and CD4+ T cells, downregulation of miR‑146a inhibited cell growth and induced apoptosis of cervical cancer cells, while overexpression of miR‑146a promoted cell growth and reduced apoptosis of cervical cancer cells. Downregulation of miR‑146a induced TRAF6 and NF‑κB protein expression, increased IL‑6, IL‑17A and IL‑21 levels, and enhanced p‑STAT3 protein expression. The inhibition of TRAF6 attenuated the effects of anti‑miR‑146a on the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis. Collectively, miR‑146a regulated the function of Th17 cell differentiation to modulate cervical cancer cell growth and apoptosis through NF‑κB signaling by targeting TRAF6. miR‑146a may function as an oncogene in cervical cancer via Th17 cell differentiation by targeting TRAF6.

Morgan JJ, McAvera RM, Crawford LJ
TRAF6 Silencing Attenuates Multiple Myeloma Cell Adhesion to Bone Marrow Stromal Cells.
Int J Mol Sci. 2019; 20(3) [PubMed] Free Access to Full Article Related Publications
The bone marrow (BM) microenvironment plays an important role in supporting proliferation, survival and drug resistance of Multiple Myeloma (MM) cells. MM cells adhere to bone marrow stromal cells leading to the activation of tumour-promoting signaling pathways. Activation of the NFκB pathway, in particular, is central to the pathogenesis of MM. Tumour necrosis factor receptor-associated factor 6 (TRAF6) is a key mediator of NFκB activation and has previously been highlighted as a potential therapeutic target in MM. Here, we demonstrate that adherence of MM cell lines to stromal cells results in a reciprocal increase in TRAF6 expression. Knockdown of TRAF6 expression attenuates the ability of MM cells to bind to stromal cells and this is associated with a decrease in NFκB-induced expression of the adhesion molecules ICAM1 and VCAM1. Finally, we show that knockdown of TRAF6 sensitizes MM cells to treatment with bortezomib when co-cultured with stromal cells. Inhibiting TRAF6 represents a promising strategy to target MM cells in the BM microenvironment.

Sun J, Zhao B, Du K, Liu P
TRAF6 correlated to invasion and poor prognosis of glioblastoma via elevating MMP9 expression.
Neuroreport. 2019; 30(2):127-133 [PubMed] Related Publications
Aberrant expression of tumor necrosis factor receptor-associated factor 6 (TRAF6) was reported in several types of cancers and it was demonstrated to promote tumor progression. In glioblastoma multiforme (GBM), TRAF6 depression by miRNA could decrease GBM cell resistance to temozolomide, but the prognostic values of TRAF6 and its functions in GBM progression have not been elucidated. In our study, the expression of TRAF6 and matrix metalloprotein 9 (MMP9) in 101 cases of GBM were investigated using immunohistochemistry. Twelve pairs of GBM frozen tissues and their corresponding adjacent tissues were collected during operation prospectively, and TRAF6 and MMP9 mRNA levels in them were detected using qRT-PCR. The correlations between TRAF6, MMP9, and clinicopathological factors were analyzed using the Chi-square test, and the prognostic value of TRAF6 and MMP9 were evaluated using univariate and multivariate analysis. The effect of TRAF6 and MMP9 on GBM cell invasion and proliferation was detected with experiments in vitro, and the correlation between TRAF6 and MMP9 expression was explored by regulating their expression with overexpression or knockdown. The expression of TRAF6 and MMP9 in GBM tissues was significantly higher than that in adjacent tissues. The expression of TRAF6 and MMP9 was significantly associated in GBM tissues. Both TRAF6 and MMP9 correlated with poor prognosis of GBM, and TRAF6 was identified as an independent prognostic factor of GBM. TRAF6 could promote invasion instead of proliferation of GBM cells via elevating expression of MMP9. TRAF6 was identified as an independent prognostic factor of GBM, with ability to promote invasion of GBM cells via elevating expression of MMP9.

Li N, Wang J, Yu W, et al.
MicroRNA‑146a inhibits the inflammatory responses induced by interleukin‑17A during the infection of Helicobacter pylori.
Mol Med Rep. 2019; 19(2):1388-1395 [PubMed] Related Publications
Helicobacter pylori (H. pylori) infection is the major cause of chronic active gastritis and peptic ulcer disease. Upregulation of IL‑17A is associated with H. pylori infection in the gastric mucosa; however, the factors involved in the regulation of interleukin (IL)‑17A‑induced inflammatory responses in H. pylori‑associated gastritis remain unknown. MicroRNAs (miRNAs) serve as key post‑transcriptional regulators of gene expression and are associated with the H. pylori infection. The present study aimed to analyze the effects of IL‑17A on the expression of miR‑146a upon infection with H. pylori, as well as to identify the possible impact of miR‑146a dysregulation on the inflammatory response in vivo and in vitro. Reverse transcription‑quantitative polymerase chain reaction analysis was used to determine the expression levels of miR‑146a in gastric epithelial cells upon IL‑17A stimulation. The effects of miR‑146a mimics on IL‑17A‑induced inflammatory responses in SGC‑7901 cells were evaluated. The effects of miR‑146a mimics on the expression levels of IL‑1 receptor‑associated kinase 1 (IRAK1) and tumor necrosis factor receptor‑associated factor 6 (TRAF6) upon IL‑17A treatment were analyzed, and the IL‑17A‑stimulated inflammation following the silencing of IRAK1 and TRAF6 was observed. In addition, the correlation between miR‑146a and IL‑17A in human gastric mucosa with H. pylori was examined. The results indicated that IL‑17A‑induced miR‑146a may regulate the inflammatory response during the infection of H. pylori in a nuclear factor‑κB‑dependent manner. Furthermore, the expression of miR‑146a and IL‑17A are positively correlated in human gastric mucosa infected with H. pylori. These data suggested that miR‑146a may serve as a biomarker or therapeutic target in gastritis therapy.

Kirchmeyer M, Servais FA, Hamdorf M, et al.
Cytokine-mediated modulation of the hepatic miRNome: miR-146b-5p is an IL-6-inducible miRNA with multiple targets.
J Leukoc Biol. 2018; 104(5):987-1002 [PubMed] Related Publications
Interleukin-6 (IL-6)-type cytokines play important roles in liver (patho-)biology. For instance, they regulate the acute phase response to inflammatory signals and are involved in hepatocarcinogenesis. Much is known about the regulation of protein-coding genes by cytokines whereas their effects on the miRNome is less well understood. We performed a microarray screen to identify microRNAs (miRNAs) in human hepatocytes which are modulated by IL-6-type cytokines. Using samples of 2 donors, 27 and 68 miRNAs (out of 1,733) were found to be differentially expressed upon stimulation with hyper-IL-6 (HIL-6) for up to 72 h, with an overlap of 15 commonly regulated miRNAs. qPCR validation revealed that miR-146b-5p was also consistently up-regulated in hepatocytes derived from 2 other donors. Interestingly, miR-146b-5p (but not miR-146a-5p) was induced by IL-6-type cytokines (HIL-6 and OSM) in non-transformed liver-derived PH5CH8 and THLE2 cells and in Huh-7 hepatoma cells, but not in HepG2 or Hep3B hepatoma cells. We did not find evidence for a differential regulation of miR-146b-5p expression by promoter methylation, also when analyzing the TCGA data set on liver cancer samples. Inducible overexpression of miR-146b-5p in PH5CH8 cells followed by RNA-Seq analysis revealed effects on multiple mRNAs, including those encoding IRAK1 and TRAF6 crucial for Toll-like receptor signaling. Indeed, LPS-mediated signaling was attenuated upon overexpression of miR-146b-5p, suggesting a regulatory loop to modulate inflammatory signaling in hepatocytes. Further validation experiments suggest DNAJC6, MAGEE1, MPHOSPH6, PPP2R1B, SLC10A3, SNRNP27, and TIMM17B to be novel targets for miR-146b-5p (and miR-146a-5p).

Wan C, Wu M, Zhang S, et al.
α7nAChR-mediated recruitment of PP1γ promotes TRAF6/NF-κB cascade to facilitate the progression of Hepatocellular Carcinoma.
Mol Carcinog. 2018; 57(11):1626-1639 [PubMed] Related Publications
The cholinergic signaling pathways have been recently implicated in the development of various human cancers. However, the underlying molecular mechanism remains largely unclear. In the present study, we reported that α7 nicotinic acetylcholine receptor (α7nAChR), an important member of nicotinic acetylcholine receptors, interacts with Protein Phosphatase-1γ (PP1γ) in human Hepatocellular Carcinoma (HCC) tissues. In addition, we found that α7nAChR facilitates the ubiquitination and activation of TRAF6 in a PP1γ-dependent manner in HCC cells. Furthermore, we showed that ligand-bounded α7nAChR induces the degradation of IκBα, leading to resultant phosphorylation and nuclear accumulation of NF-κB p65. Accordingly, acetylcholine triggers the expression of critical NF-κB target genes, such as Cyclin D1 and PCNA, as well as the proliferation of HCC cells in a PP1γ- and α7nAChR-dependent manner. Furthermore, we revealed that nicotine-triggered α7nAChR activation promotes oncosphere formation and in vivo tumor growth of HCC cells. Moreover, we showed that the protein levels of both α7nAChR and PP1γ are significantly upregulated in human HCC specimens compared with adjacent non-cancerous ones, and that upregulated expression of the two proteins predict significantly worsened prognosis in HCC patients. These findings together indicate that the cholinergic receptor α7nAChR exerts a facilitating role in HCC development through PP1γ-dependent TRAF6/NF-κB signaling.

Kong L, Li X, Wang H, et al.
Calycosin inhibits nasopharyngeal carcinoma cells by influencing EWSAT1 expression to regulate the TRAF6-related pathways.
Biomed Pharmacother. 2018; 106:342-348 [PubMed] Related Publications
The incidence of nasopharyngeal carcinoma (NPC) in China is relatively higher than that throughout the rest of the world, and NPC is geographically distributed. Long non-coding RNA (lncRNA) plays a key role in the development of tumors. Recent studies have found that the lncRNA Ewing sarcoma-associated transcript 1 (EWSAT1) is highly expressed in various tumors and also in NPCs. The isoflavone calycosin, which is a typical Chinese herbal medicine, can inhibit the growth of breast cancer, colorectal cancer, osteosarcoma and other cancers. The aim of our study was to select NPCs that were sensitive to calycosin and whether calycosin had an effect on NPC cells. If it does, are the effects related to a high expression of EWSAT1? We also verified that EWSAT1 was highly expressed in NPC cells. At the same time, we found that calycosin inhibited the growth of NPC cell lines. To further determine whether the effect of calycosin on NPC cells was related to EWSAT1, we used NPC cells with different concentrations of calycosin and found that the expression of EWSAT1 decreased significantly with increasing concentrations of calycosin and that the expression of downstream factors and pathways were also affected. It was demonstrated that calycosin affected NPC cell growth by regulating EWSAT1 and its downstream pathway. In addition, we overexpressed EWSAT1 and found that the increased expression of EWSAT1 weakened the growth inhibitory effect of calycosin on NPC cells.

Zhang B, Fu D, Xu Q, et al.
The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1.
Nat Commun. 2018; 9(1):1723 [PubMed] Free Access to Full Article Related Publications
The senescence-associated secretory phenotype (SASP) can be provoked by side effects of therapeutic agents, fueling advanced complications including cancer resistance. However, the intracellular signal network supporting initiation and development of the SASP driven by treatment-induced damage remains unclear. Here we report that the transcription factor Zscan4 is elevated for expression by an ATM-TRAF6-TAK1 axis during the acute DNA damage response and enables a long term SASP in human stromal cells. Further, TAK1 activates p38 and PI3K/Akt/mTOR to support the persistent SASP signaling. As TAK1 is implicated in dual feedforward mechanisms to orchestrate the SASP development, pharmacologically targeting TAK1 deprives cancer cells of resistance acquired from treatment-damaged stromal cells in vitro and substantially promotes tumour regression in vivo. Together, our study reveals a novel network that links functionally critical molecules associated with the SASP development in therapeutic settings, thus opening new avenues to improve clinical outcomes and advance precision medicine.

Hu Q, Song J, Ding B, et al.
miR-146a promotes cervical cancer cell viability via targeting IRAK1 and TRAF6.
Oncol Rep. 2018; 39(6):3015-3024 [PubMed] Related Publications
Cervical cancer is the third most common type of cancer in women, and microRNAs play an important role in this type of cancer. The elevated expression of miR-146a is involved in the pathogenesis of cancers generally, but its role in cervical cancer has not been fully elucidated. In the present study, we assessed the expression of miR-146a in G>C polymorphisms and confirmed that the overexpression of miR-146a promoted cervical cancer cell viability. The recombinant expression plasmids pre-miR-146a-G or pre-miR-146a-C including single nucleotide polymorphisms (SNP) were successfully constructed. Pre-miR-146a-G or pre-miR-146a-C was transfected into cervical cancer cells or immortalized non-tumorigenic cells and the expression of miR-146a was evaluated by real-time PCR. The cell viability, cell-cycle analysis and apoptosis were assessed using Cell Counting Kit-8 assay (CCK-8), flow cytometry and cleaved caspase-3 protein expression, respectively. The expression of interleukin 1 receptor associated kinase 1 (IRAK1), TNF receptor-associated factor 6 (TRAF6) and cyclin D1 was assessed following the transfection with a miR-146a mimic or a negative control. The cell viability and the number of S-phase cells increased after transfection with miR-146a mimic or an IRAK1 or TRAF6 interference fragment. After transfection, IRAK1 and TRAF6 protein expression was downregulated and the expression of cyclin D1 was upregulated, however apoptosis and cleaved caspase-3 were not affected. Polymorphisms in miR-146a precursor may be linked to the expression of miR-146a and may be a potential target for cervical cancer therapy.

Zhao H, Li H
Network-based meta-analysis in the identification of biomarkers for papillary thyroid cancer.
Gene. 2018; 661:160-168 [PubMed] Related Publications
Papillary thyroid carcinoma (PTC) has been increasing across the world with incomplete understanding of its pathogenesis. We aimed to investigate gene alterations and biomarkers contributing to PTC development. A total of five eligible microarray datasets including 94 PTC and 81 normal thyroid samples were included to identify gene expression signatures. Using integrative meta-analysis of expression data (INMEX) program, we identified a total of 2699 differentially expressed genes (DEGs) (1333 overexpressed and 1366 underexpressed genes) in PTC relative to normal thyroid samples. The top 100 upregualted and downregulated DEGs identified in the meta-analysis were further validated in The Cancer Genome Atlas (TCGA) dataset for PTC with high consistency. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed pathways in cancer, proteoglycans in cancer, focal adhesion, axon guidance, and ECM-receptor interaction among the top 5 most enriched pathways. Network-based meta-analysis identified FN1 and TRAF6 to be the most highly ranked hub genes among the overexpressed and underexpressed genes, respectively, both of which are involved in pathways in cancer. The most enriched terms for Gene Ontology (GO) of biological processes, cellular component, and molecular function were signal transduction, cytoplasm, and protein binding, respectively. Our meta-analysis comprehensively investigated DEGs, hub genes, enriched pathways and GO terms for PTC, which might provide additional approaches to explore the molecular mechanisms underlying the pathophysiology of PTC, and identify biomarkers and therapeutic targets toward PTC.

Liang Y, Jiao J, Liang L, et al.
Tumor necrosis factor receptor-associated factor 6 mediated the promotion of salivary adenoid cystic carcinoma progression through Smad-p38-JNK signaling pathway induced by TGF-β.
J Oral Pathol Med. 2018; 47(6):583-589 [PubMed] Related Publications
BACKGROUND: Tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) has been proved to play an important role in tumorigenesis, invasion, and metastasis. However, its precise role salivary adenoid cystic carcinoma (SACC) has not been determined. The aim of this study was to explore the role of TRAF6 in SACC including invasion and metastasis of SACC cells.
MATERIALS AND METHODS: Immunohistochemistry and quantitative real-time PCR were performed in SACC tissues paired with their adjacent normal tissues to analyze the expression of TRAF6. Downstream proteins expression was explored when TRAF6 was knockdown by siRNA.
RESULTS: The results show that TRAF6 is upregulated in SACC samples, especially in SACC with metastasis, which is closely correlated with an aggressive phenotype (P = .0073) and shorter life survival span (P = .0061) in SACC patients. Knockdown of TRAF6 can attenuate the promotion effect of SACC cell invasion induced by TGF-β. Western blot results also showed that silencing TRAF6 expression can inhibit the activation of SMAD2, SMAD3, ERK, p38, and JNK induced by TGF-β in SACC cells.
CONCLUSION: These data suggested that TRAF6 regulates TGF-β-mediated SACC progression through SMAD2/3-ERK-p38-JNK cascades.

Bouraoui Y, Achour M, Royuela M, Oueslati R
Immune profiling of human prostate epithelial cells determined by expression of p38/TRAF-6/ERK MAP kinases pathways.
Kaohsiung J Med Sci. 2018; 34(3):125-133 [PubMed] Related Publications
The aim of the present work was to study the immune profiling of prostate epithelial cells by the expression of ASK-1/p38 and Raf-1/ERK MAP Kinases signaling pathways mediated by TRAF-6. Immunohistochemical and Western blot analyses for TRAF-6, ASK-1, MEK-6, p38, Raf-1, MEK-1, ERK-1, ERK-2 and PSA were carried out in 5 samples of normal prostate gland, 24 samples of BPH and 19 samples of PC. Immunoreaction to TRAF-6 was found in the cytoplasm of epithelial cells of BPH and tumor cells of PC samples. For patients with the profile (TRAF-6+), optical densities revealed a weak immunoexpression of ASK-1 in PC compared to BPH patients. Whereas, immunoexpression to Raf-1 was higher in PC than in BPH. According to the expression of ASK-1 and Raf-1, two main profiles were identified: (TRAF-6+, ASK-1+, Raf-1+) and (TRAF-6+, ASK-1+, RAF-1-) in both BPH and PC. In addition, ASK-1/p38 axis expression was increased in BPH. Raf-1/ERK signaling pathway was increased in PC samples. On the other hand, representing of individual signaling protein expression enclosing each of p38 and ERK MAP Kinases according to TRAF-6+ showed a qualitative behavior of ASK61/p38 and Raf-1/ERK signaling pathways and a dynamic expression of PSA associated with immune and inflammatory process. These findings suggest that prostate epithelial cell could able an immune and inflammatory setting.

Bao X, Shi J, Xie F, et al.
Proteolytic Release of the p75
Cancer Res. 2018; 78(9):2262-2276 [PubMed] Related Publications
Resistance to anoikis allows cancer cells to survive during systemic circulation; however, the mechanism underlying anoikis resistance remains unclear. Here we show that A disintegrin and metalloprotease 10 (ADAM10)-mediated cleavage of p75 neurotrophin receptor (p75

Meng Q, Zhang W, Xu X, et al.
The effects of TRAF6 on proliferation, apoptosis and invasion in osteosarcoma are regulated by miR-124.
Int J Mol Med. 2018; 41(5):2968-2976 [PubMed] Related Publications
The present study aimed to verify tumor necrosis factor receptor‑associated factor 6 (TRAF6) as the target gene of microRNA-124 (miR-124). In addition, the expression of miR‑124 was investigated in osteosarcoma tissues and cells, and its effects on the biological characteristics of osteosarcoma cells were determined, in order to provide an experimental and theoretical basis for the application of TRAF6 in the treatment of osteosarcoma. A fluorescence reporter enzyme system was used to verify TRAF6 as a target gene of miR‑124, and western blotting was used to detect the effects of miR‑124 on the protein expression levels of TRAF6 in cells. The expression levels of miR‑124 were detected in osteosarcoma tissues and an osteosarcoma cell line (MG‑63) by quantitative polymerase chain reaction (qPCR). In addition, a total of 48 h post‑transfection of MG‑63 cells with a miR‑124 mimic, qPCR was used to detect the expression levels of miR‑124, and the effects of miR‑124 on the viability of MG‑63 human osteosarcoma cells was determined using the MTT method. The effects of miR‑124 on the cell cycle progression and apoptosis of MG‑63 cells were analyzed by flow cytometry, whereas the effects of miR‑124 on the migration of MG‑63 cells was detected using the Transwell invasion chamber analysis method. A TRAF6 recombinant expression plasmid (pcDNA3.1‑TRAF6) was also constructed, and MG‑63 cells were transfected with the recombinant plasmid and a miR‑124 mimic, in order to further validate the biological role of miR‑124 via the regulation of TRAF6. The results of the present study indicated that, compared with in the normal control group, the expression levels of miR‑124 were significantly increased in MG‑63 cells transfected with a miR‑124 mimic (P<0.01). In addition, the luciferase reporter gene system demonstrated that, compared with in the control group, relative luciferase activity was significantly reduced in the miR‑124 mimic group (P<0.01). The results of MTT analysis indicated that cell viability was also significantly reduced in response to the overexpression of miR‑124 in MG‑63 cells (P<0.01). Flow cytometric analysis demonstrated that the proportion of cells in S phase and G2/M phase was significantly decreased (P<0.01) in cells overexpressing miR‑124, and the number of apoptotic cells was significantly increased (P<0.01). Furthermore, the results of the Transwell invasion assay suggested that the number of invasive cells was significantly decreased following enhanced expression of miR‑124 (P<0.01). In MG‑63 cells overexpressing miR‑124 and TRAF6, the results of MTT, flow cytometric and Transwell assay analyses demonstrated that the overexpression of TRAF6 had the opposite biological effects compared to miR‑124 overexpression. In conclusion, the present study indicated that the expression levels of miR‑124 were downregulated in human osteosarcoma tissues and cells, and that miR‑124 is associated with negative regulation of TRAF6 expression; therefore, the role of TRAF6 in primary osteosarcoma may be regulated by miR‑124. Therapeutic strategies that enhance miR‑124 expression or inhibit TRAF6 expression may be beneficial for the treatment of patients with osteosarcoma.

Qian Z, Zhou S, Zhou Z, et al.
miR‑146b‑5p suppresses glioblastoma cell resistance to temozolomide through targeting TRAF6.
Oncol Rep. 2017; 38(5):2941-2950 [PubMed] Related Publications
Temozolomide (TMZ), as a kind of alkylating agent, is widely utilized for the treatment of glioblastoma (GBM). However, temozolomide resistance (TR) often develops quickly and results in tumor recurrence and poor outcome. Recent advances have demonstrated that miRNAs exert critical roles in chemoresistance. Downregulation of miR‑146b‑5p promotes glioma cell proliferation, reduces apoptosis, and correlates with poor survival of patients. Nonetheless, the function of miR‑146b‑5p in temozolomide resistance remains unclear. In the present study, we successfully generated U87 and U251‑TR cells, and found that miR‑146b‑5p was downregulated in TR cells. Overexpression of miR‑146b‑5p restored sensitivity of U87/U251‑TR cells to TMZ by targeting tumor necrosis factor receptor-associated factor 6 (TRAF6). The levels of TRAF6 were inversely related to miR‑146b‑5p levels, and overexpression of TRAF6 in miR‑146b‑5p‑OE cells enhanced the resistance against TMZ. Moreover, temozolomide-resistant GBM cells had a higher level of phosphorylated protein kinase B (AKT) and P65. Overexpression of miR‑146b‑5p or TRAF6 knockdown significantly decreased the level of p‑AKT and p‑p65. Collectively, our data demonstrated that miR‑146b‑5p, as a tumor suppressor, mediated temozolomide resistance in GBM cells through negatively regulating TRAF6 expression, indicating that miR‑146b‑5p and its targeted genes would be potential therapeutic targets for glioma therapy.

Min SK, Jung SY, Kang HK, et al.
Functional diversity of miR-146a-5p and TRAF6 in normal and oral cancer cells.
Int J Oncol. 2017; 51(5):1541-1552 [PubMed] Related Publications
Numerous studies implicate miR-146a as pleiotropic regulator of carcinogenesis; however, its roles in carcinogenesis are not fully understood. A clue from expression analyses of miR-146a-5p in all 13 oral squamous cell carcinoma (OSCC) cell lines examined and in OSCC tissues, whole blood and whole saliva of OSCC patients in vivo revealed that miR‑146a-5p expression was highly upregulated. Particularly, we widened the view of its upregulation in saliva, implicating that high miR-146a-5p expression is not only correlated closely to the development of human oral cancer, but also to a possible candidate as a diagnostic marker of OSCC. Indeed, further examination showed that exogenous miR-146a-5p expression showed pleiotropic effects on cell proliferation and apoptosis which were partially based on the contextual responses of activation of JNK, downstream of TRAF6 that was targeted by miR-146a-5p in normal human keratinocytes and OSCC cell lines. TRAF6 suppression by a TRAF6-specific siRNA resulted in contradictory consequences on cellular processes in normal and OSCC cells. Notably, TRAF6 downregulation by both miR-146a-5p and TRAF6-specific siRNA deactivated JNK in SCC-9, but not in normal human keratinocytes. In support of the proliferation-promoting effect of miR-146a-5p, silencing of endogenous miR-146a-5p significantly reduced proliferation of SCC-9. Together, these results suggest that miR-146a-5p affects proliferation and apoptosis in a cellular context-dependent manner and selectively disarms the TRAF6-mediated branch of the TGF-β signaling in OSCC cell lines by sparing Smad4 involvement.

Kumari P, Saha I, Narayanan A, et al.
Essential role of HCMV deubiquitinase in promoting oncogenesis by targeting anti-viral innate immune signaling pathways.
Cell Death Dis. 2017; 8(10):e3078 [PubMed] Free Access to Full Article Related Publications
Cancer is a multifactorial disease and virus-mediated carcinogenesis is one of the crucial factors, which is poorly understood. Human cytomegalovirus (HCMV) is a herpesvirus and its components have been evidenced to be associated with cancer of different tissue origin. However, its role in cancer remains unknown. Here, we identified a conserved herpesviral tegument protein known as pUL48 of HCMV, encoding deubiquitinase enzyme, as having a key role in carcinogenesis. We show using deubiquitinase sufficient- and deficient-HCMV that HCMV deubiquitinase is a key in inducing enhanced cellular metabolic activity through upregulation of several anti-apoptotic genes and downregulation of several pro-apoptotic genes expression. Furthermore, HCMV deubiquitinase acquires pro-tumor functions by inhibiting PRR-mediated type I interferon via deubiquitination of TRAF6, TRAF3, IRAK1, IRF7 and STING. Taken together, our results suggest that HCMV infection may promote oncogenesis by inhibiting innate immunity of the host.

Wang B, Zhao H, Zhao L, et al.
Up-regulation of OLR1 expression by TBC1D3 through activation of TNFα/NF-κB pathway promotes the migration of human breast cancer cells.
Cancer Lett. 2017; 408:60-70 [PubMed] Related Publications
Metastatic spread of cancer cells is the most life-threatening aspect of breast cancer and involves multiple steps including cell migration. We recently found that the TBC1D3 oncogene promotes the migration of breast cancer cells, and its interaction with CaM enhances the effects of TBC1D3. However, little is known regarding the mechanism by which TBC1D3 induces the migration of cancer cells. Here, we demonstrated that TBC1D3 stimulated the expression of oxidized low density lipoprotein receptor 1 (OLR1), a stimulator of cell migration, in breast cancer cells at the transcriptional level. Depletion of OLR1 by siRNAs or down-regulation of OLR1 expression using pomalidomide, a TNFα inhibitor, significantly decreased TBC1D3-induced migration of these cells. Notably, TBC1D3 overexpression activated NF-κB, a major effector of TNFα signaling, while inhibition of TNFα signaling suppressed the effects of TBC1D3. Consistent with this, NF-κB inhibition using its specific inhibitor caffeic acid phenethyl ester decreased both TBC1D3-induced OLR1 expression and cell migration, suggesting a critical role for TNFα/NF-κB signaling in TBC1D3-induced migration of breast cancer cells. Mechanistically, TBC1D3 induced activation of this signaling pathway on multiple levels, including by increasing the release of TNFα, elevating the transcription of TNFR1, TRAF1, TRAF5 and TRAF6, and decreasing the degradation of TNFR1. In summary, these studies identify the TBC1D3 oncogene as a novel regulator of TNFα/NF-κB signaling that mediates this oncogene-induced migration of human breast cancer cells by up-regulating OLR1.

Magilnick N, Reyes EY, Wang WL, et al.
Proc Natl Acad Sci U S A. 2017; 114(34):E7140-E7149 [PubMed] Free Access to Full Article Related Publications

Karki R, Malireddi RKS, Zhu Q, Kanneganti TD
NLRC3 regulates cellular proliferation and apoptosis to attenuate the development of colorectal cancer.
Cell Cycle. 2017; 16(13):1243-1251 [PubMed] Free Access to Full Article Related Publications
Nucleotide-binding domain, leucine-rich-repeat-containing proteins (NLRs) are intracellular innate immune sensors of pathogen-associated and damage-associated molecular patterns. NLRs regulate diverse biologic processes such as inflammatory responses, cell proliferation and death, and gut microbiota to attenuate tumorigenesis. In a recent publication in Nature, we identified NLRC3 as a negative regulator of PI3K-mTOR signaling and characterized its potential tumor suppressor function. Enterocytes lacking NLRC3 cannot control cellular proliferation because they are unable to suppress activation of PI3K-mTOR signaling pathways. In this Extra-View, we explore possible mechanisms through which NLRC3 regulates cellular proliferation and cell death. Besides interacting with PI3K, NLRC3 associates with TRAF6 and mTOR, confirming our recent finding that NLRC3 negatively regulates the PI3K-mTOR axis. Herein, we show that NLRC3 suppresses c-Myc expression and activation of PI3K-AKT targets FoxO3a and FoxO1 in the colon of Nlrc3

Bedini A, Baiula M, Vincelli G, et al.
Nociceptin/orphanin FQ antagonizes lipopolysaccharide-stimulated proliferation, migration and inflammatory signaling in human glioblastoma U87 cells.
Biochem Pharmacol. 2017; 140:89-104 [PubMed] Related Publications
Glioblastoma is among the most aggressive brain tumors and has an exceedingly poor prognosis. Recently, the importance of the tumor microenvironment in glioblastoma cell growth and progression has been emphasized. Toll-like receptor 4 (TLR4) recognizes bacterial lipopolysaccharide (LPS) and endogenous ligands originating from dying cells or the extracellular matrix involved in host defense and in inflammation. G-protein coupled receptors (GPCRs) have gained interest in anti-tumor drug discovery due to the role that they directly or indirectly play by transactivating other receptors, causing cell migration and proliferation. A proteomic analysis showed that the nociceptin receptor (NOPr) is among the GPCRs significantly expressed in glioblastoma cells, including U87 cells. We describe a novel role of the peptide nociceptin (N/OFQ), the endogenous ligand of the NOPr that counteracts cell migration, proliferation and increase in IL-1β mRNA elicited by LPS via TLR4 in U87 glioblastoma cells. Signaling pathways through which N/OFQ inhibits LPS-mediated cell migration and elevation of [Ca

Wang P, Cao J, Liu S, et al.
Upregulated microRNA-429 inhibits the migration of HCC cells by targeting TRAF6 through the NF-κB pathway.
Oncol Rep. 2017; 37(5):2883-2890 [PubMed] Related Publications
Increasing evidence indicates that miR-429 is involved in tumor suppression in various human cancers. however, its role in hepatocellular carcinoma (HCC) remains unclear. In the present study, we found that miR-429 was significantly downregulated in HCC tissue samples and cell lines. Upregulation of miR-429 markedly suppressed proliferation and migration of HCC cells. Moreover, we identified TRAF6 as a direct target of miR-429. Downregulation of TRAF6 partially attenuated the oncogenic effect of anti‑miR-429 on HCC cells. Ectopic expression of miR-429 in HCC cells inhibited TCF-4 activity as well as nuclear accumulation of P65 and expression of the NF-κB targets c-Myc and phosphorylation of TAK1. In a nude xenograft model, miR-429 upregulation significantly decreased HCC growth. In conclusion, by targeting TRAF6, miR-429 is downregulated in HCC and inhibits HCC cell proliferation and motility. Our data suggest that miR-429 may serve as a potential anticancer target for the treatment of HCC.

Li C, Miao R, Liu S, et al.
Down-regulation of miR-146b-5p by long noncoding RNA MALAT1 in hepatocellular carcinoma promotes cancer growth and metastasis.
Oncotarget. 2017; 8(17):28683-28695 [PubMed] Free Access to Full Article Related Publications
MicroRNAs play an important role in liver cancer genesis and progression. In this study, we identified down-regulation of miR-146b-5p associated with tumor growth, metastasis and poor survival in hepatocellular carcinoma (HCC) patients. miR-146b-5p could suppress proliferation, migration, and invasion and induced apoptosis in vitro and in vivo. Remarkably, TNF receptor associated factor 6 (TRAF6) was confirmed as a direct target of miR-146b-5p in HCC and miR-146b-5p exerted the tumor suppression roles through inhibiting the phosphorylation of Akt mediated by TRAF6. Furthermore, we identified long non-coding RNA MALAT1 as a molecular sponge of miR-146b-5p to down-regulate its expression in HCC. In general, our results indicate that miR-146b-5p inhibits tumor growth and metastasis of HCC by targeting TRAF6 mediated Akt phosphorylation.

Zhang X, Zhu C, Wang T, et al.
GP73 represses host innate immune response to promote virus replication by facilitating MAVS and TRAF6 degradation.
PLoS Pathog. 2017; 13(4):e1006321 [PubMed] Free Access to Full Article Related Publications
Hepatitis C virus (HCV) infection is a leading cause of chronic liver diseases and hepatocellular carcinoma (HCC) and Golgi protein 73 (GP73) is a serum biomarker for liver diseases and HCC. However, the mechanism underlying GP73 regulates HCV infection is largely unknown. Here, we revealed that GP73 acts as a novel negative regulator of host innate immunity to facilitate HCV infection. GP73 expression is activated and correlated with interferon-beta (IFN-β) production during HCV infection in patients' serum, primary human hepatocytes (PHHs) and human hepatoma cells through mitochondrial antiviral signaling protein (MAVS), TNF receptor-associated factor 6 (TRAF6) and mitogen-activated protein kinase kinase/extracellular regulated protein kinase (MEK/ERK) pathway. Detailed studies revealed that HCV infection activates MAVS that in turn recruits TRAF6 via TRAF-interacting-motifs (TIMs), and TRAF6 subsequently directly recruits GP73 to MAVS via coiled-coil domain. After binding with MAVS and TRAF6, GP73 promotes MAVS and TRAF6 degradation through proteasome-dependent pathway. Moreover, GP73 attenuates IFN-β promoter, IFN-stimulated response element (ISRE) and nuclear factor κB (NF-κB) promoter and down-regulates IFN-β, IFN-λ1, interleukin-6 (IL-6) and IFN-stimulated gene 56 (ISG56), leading to the repression of host innate immunity. Finally, knock-down of GP73 down-regulates HCV infection and replication in Huh7-MAVSR cells and primary human hepatocytes (PHHs), but such repression is rescued by GP73m4 (a mutant GP73 resists to GP73-shRNA#4) in Huh7-MAVSR cells, suggesting that GP73 facilitates HCV infection. Taken together, we demonstrated that GP73 acts as a negative regulator of innate immunity to facilitate HCV infection by interacting with MAVS/TRAF6 and promoting MAVS/TRAF6 degradation. This study provides new insights into the mechanism of HCV infection and pathogenesis, and suggests that GP73 is a new potential antiviral target in the prevention and treatment of HCV associated diseases.

Qian CN, Mei Y, Zhang J
Cancer metastasis: issues and challenges.
Chin J Cancer. 2017; 36(1):38 [PubMed] Free Access to Full Article Related Publications
Metastasis is the major cause of treatment failure in cancer patients and of cancer-related deaths. This editorial discusses how cancer metastasis may be better perceived and controlled. Based on big-data analyses, a collection of 150 important pro-metastatic genes was studied. Using The Cancer Genome Atlas datasets to re-analyze the effect of some previously reported metastatic genes-e.g., JAM2, PPARGC1A, SIK2, and TRAF6-on overall survival of patients with renal and liver cancers, we found that these genes are actually protective factors for patients with cancer. The role of epithelial-mesenchymal transition (EMT) in single-cell metastasis has been well-documented. However, in metastasis caused by cancer cell clusters, EMT may not be necessary. A novel role of epithelial marker E-cadherin, as a sensitizer for chemoresistant prostate cancer cells by inhibiting Notch signaling, has been found. This editorial also discusses the obstacles for developing anti-metastatic drugs, including the lack of high-throughput technologies for identifying metastasis inhibitors, less application of animal models in the pre-clinical evaluation of the leading compounds, and the need for adjustments in clinical trial design to better reflect the anti-metastatic efficacy of new drugs. We are confident that by developing more effective high-throughput technologies to identify metastasis inhibitors, we can better predict, prevent, and treat cancer metastasis.

Qi Y, Pradipta AR, Li M, et al.
Cinchonine induces apoptosis of HeLa and A549 cells through targeting TRAF6.
J Exp Clin Cancer Res. 2017; 36(1):35 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cancer cells are known to over-express TRAF6 that is critical for both AKT and TAK1 activations. The Really Interesting New Gene (RING) domain of TRAF6 is believed to be responsible for the E3 ligase activity, ZINC fingers of TRAF6 provide critical support for the activity of the RING domain which is critical for both AKT and TAK1 activations.
METHODS: We employed computational docking program to identify small molecules that could effectively and competitively bind with the RING domain of TRAF6, which is believed to be responsible for its E3 ligase activity. MTT assay and flow cytometry were employed to analyze apoptosis of cancer cells. Signaling pathways were detected using immunoprecipitation and western blotting, and immunofluorescence was pursued to assess the nature of binding of cinchonine to TRAF6. We also performed animal experiments to test effect of cinchonine in vivo.
RESULTS: Cinchonine, a naturally occurring Cinchona alkaloid identified from the docking study, could bind to TRAF6 in HeLa and A549 cells and induce apoptosis of these cancer cells. We found that AKT ubiquitination and phosphorylation as well as phosphorylation of TAK1 were decreased. These activities would lead to subsequent suppression anti-apoptotic protein Bcl-2, while elevating pro-apoptotic protein Bax. Immunofluorescence staining unambiguously demonstrated the binding of cinchonine specifically at the RING domain of TRAF6 in cells, thereby validating the computational modeling. Animal experiments showed that cinchonine could suppress tumor growth in mice without showing significant acute toxicity.
CONCLUSION: These investigations suggest that through competitive binding with the RING domain of TRAF6, cinchonine could induce apoptosis via inhibiting AKT and TAK1 signaling pathways.

Chen H, Li M, Sanchez E, et al.
Combined TRAF6 Targeting and Proteasome Blockade Has Anti-myeloma and Anti-Bone Resorptive Effects.
Mol Cancer Res. 2017; 15(5):598-609 [PubMed] Related Publications
TNF receptor-associated factor 6 (TRAF6) has been implicated in polyubiquitin-mediated IL1R/TLR signaling through activation of

Rezaeian AH, Li CF, Wu CY, et al.
A hypoxia-responsive TRAF6-ATM-H2AX signalling axis promotes HIF1α activation, tumorigenesis and metastasis.
Nat Cell Biol. 2017; 19(1):38-51 [PubMed] Free Access to Full Article Related Publications
The understanding of how hypoxia stabilizes and activates HIF1α in the nucleus with related oncogenic signals could revolutionize targeted therapy for cancers. Here, we find that histone H2AX displays oncogenic activity by serving as a crucial regulator of HIF1α signalling. H2AX interacts with HIF1α to prevent its degradation and nuclear export in order to allow successful VHL-independent HIF1α transcriptional activation. We show that mono-ubiquitylation and phosphorylation of H2AX, which are strictly mediated by hypoxia-induced E3 ligase activity of TRAF6 and ATM, critically regulate HIF1α-driven tumorigenesis. Importantly, TRAF6 and γH2AX are overexpressed in human breast cancer, correlate with activation of HIF1α signalling, and predict metastatic outcome. Thus, TRAF6 and H2AX overexpression and γH2AX-mediated HIF1α enrichment in the nucleus of cancer cells lead to overactivation of HIF1α-driven tumorigenesis, glycolysis and metastasis. Our findings suggest that TRAF6-mediated mono-ubiquitylation and subsequent phosphorylation of H2AX may serve as potential means for cancer diagnosis and therapy.

Yin Z, Cui Z, Ren Y, et al.
MiR-146a polymorphism correlates with lung cancer risk in Chinese nonsmoking females.
Oncotarget. 2017; 8(2):2275-2283 [PubMed] Free Access to Full Article Related Publications
This study provides evidence that the common rs2910164 polymorphism in miR-146a strongly correlates with lung cancer risk in nonsmoking females in northeast China. The genotypes of miR-146a rs2910164 were determined in 1131 patients with lung cancer and 1003 healthy control subjects. Tissue samples were used to evaluate the association between miRNA expression and lung cancer risk as well as the correlation between rs2910164 genotypes and miR-146a expression. The secondary structures of the wild-type and variant miR-146a sequences were predicted, and luciferase-based target assays were used to test whether miR-146a bound to tumor necrosis factor receptor associated factor 6 (TRAF6) mRNA. Individuals carrying heterozygous CG genotype of miR-146a rs2910164 had less risk of lung cancer than those carrying homozygous wild CC genotype (OR = 0.76, 95% CI = 0.60-0.98, P = 0.032). We found no significant association between miR-146a expression and lung cancer risk. MiR-146a expression differed in those carrying the CC genotype as compared with the CG or the GG genotype (P = 0.032 and 0.001), and the secondary structure of the C allele differed slightly from the G allele. Significantly lower levels of luciferase activity were observed when the TRAF6 3'UTR was cotransfected with miR-146a-3p carrying the rs2910164 C allele (P = 0.001). Thus, miR-146a rs2910164 polymorphism may influence susceptibility to lung cancer in Chinese nonsmoking females through targeting TRAF6.

Lu W, Liu S, Li B, et al.
SKP2 loss destabilizes EZH2 by promoting TRAF6-mediated ubiquitination to suppress prostate cancer.
Oncogene. 2017; 36(10):1364-1373 [PubMed] Free Access to Full Article Related Publications
EZH2 is crucial for the progression of prostate cancer (PCa) and castration-resistant prostate cancer (CRPC) through upregulation and activation of progenitor genes, as well as androgen receptor (AR)-target genes. However, the mechanisms by which EZH2 is regulated in PCa and CRPC remain elusive. Here we report that EZH2 is post-transcriptionally regulated by SKP2 in vitro in cultured cells and in vivo in mouse models. We observed aberrant upregulation of Skp2, Ezh2 and histone H3 lysine 27 trimethylation (H3K27me3) in both Pten null mouse embryonic fibroblasts (MEFs) and Pten null mouse prostate tissues. Loss of Skp2 resulted in a striking decrease of Ezh2 levels in Pten/Trp53 double-null MEFs and in prostate tumors of Pten/Trp53 double-null mutant mice. SKP2 knockdown decreased EZH2 levels in human PCa cells through upregulation of TRAF6-mediated and lysine(K) 63-linked ubiquitination of EZH2 for degradation. Ectopic expression of TRAF6 promoted the K63-linked ubiquitination of EZH2 to decrease EZH2 and H3K27me3 levels in PCa cells. In contrast, TRAF6 knockdown resulted in a reduced EZH2 ubiquitination with an increase of EZH2 and H3K27me3 levels in PCa cells. Furthermore, the catalytically dead mutant TRAF6 C70A abolished the TRAF6-mediated polyubiquitination of recombinant human EZH2 in vitro. Most importantly, a concurrent elevation of Skp2 and Ezh2 was found in CRPC tumors of Pten/Trp53 mutant mice, and expression levels of SKP2 and EZH2 were positively correlated in human PCa specimens. Taken together, our findings revealed a novel mechanism on EZH2 ubiquitination and an important signaling network of SKP2-TRAF6-EZH2/H3K27me3, and targeting SKP2-EZH2 pathway may be a promising therapeutic strategy for CRPC treatment.

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