TANK

Gene Summary

Gene:TANK; TRAF family member associated NFKB activator
Aliases: ITRAF, TRAF2, I-TRAF
Location:2q24.2
Summary:The TRAF (tumor necrosis factor receptor-associated factor) family of proteins associate with and transduce signals from members of the tumor necrosis factor receptor superfamily. The protein encoded by this gene is found in the cytoplasm and can bind to TRAF1, TRAF2, or TRAF3, thereby inhibiting TRAF function by sequestering the TRAFs in a latent state in the cytoplasm. For example, the protein encoded by this gene can block TRAF2 binding to LMP1, the Epstein-Barr virus transforming protein, and inhibit LMP1-mediated NF-kappa-B activation. Three alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:TRAF family member-associated NF-kappa-B activator
Source:NCBIAccessed: 01 September, 2019

Ontology:

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

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 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.

  • I-kappa B Kinase
  • Bladder Cancer
  • RNA Interference
  • Receptors, Tumor Necrosis Factor
  • VEGFA
  • Breast Cancer
  • Protein Binding
  • Signal Transducing Adaptor Proteins
  • Gene Expression Regulation
  • Cell Proliferation
  • TNF Receptor-Associated Factor 1
  • Mutation
  • Cancer Gene Expression Regulation
  • Western Blotting
  • Neoplasm Proteins
  • NF-kappa B
  • JNK Mitogen-Activated Protein Kinases
  • Lung Cancer
  • TNF Receptor-Associated Factor 2
  • AKT1
  • Gene Expression Profiling
  • Viral Proteins
  • Enzyme Activation
  • Phosphorylation
  • Molecular Sequence Data
  • Transfection
  • Messenger RNA
  • B-Lymphocytes
  • Protein-Serine-Threonine Kinases
  • Immunohistochemistry
  • Proteins
  • RTPCR
  • Cell Survival
  • Genes, Reporter
  • Cell Line
  • TNF
  • Apoptosis
  • Chromosome 2
  • TNF Receptor-Associated Factor 3
  • Viral Matrix Proteins
  • siRNA
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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: TANK (cancer-related)

Lee RS, Zhang L, Berger A, et al.
Characterization of the ERG-regulated Kinome in Prostate Cancer Identifies TNIK as a Potential Therapeutic Target.
Neoplasia. 2019; 21(4):389-400 [PubMed] Free Access to Full Article Related Publications
Approximately 50% of prostate cancers harbor the TMPRSS2:ERG fusion, resulting in elevated expression of the ERG transcription factor. Despite the identification of this subclass of prostate cancers, no personalized therapeutic strategies have achieved clinical implementation. Kinases are attractive therapeutic targets as signaling networks are commonly perturbed in cancers. The impact of elevated ERG expression on kinase signaling networks in prostate cancer has not been investigated. Resolution of this issue may identify novel therapeutic approaches for ERG-positive prostate cancers. In this study, we used quantitative mass spectrometry-based kinomic profiling to identify ERG-mediated changes to cellular signaling networks. We identified 76 kinases that were differentially expressed and/or phosphorylated in DU145 cells engineered to express ERG. In particular, the Traf2 and Nck-interacting kinase (TNIK) was markedly upregulated and phosphorylated on multiple sites upon ERG overexpression. Importantly, TNIK has not previously been implicated in prostate cancer. To validate the clinical relevance of these findings, we characterized expression of TNIK and TNIK phosphorylated at serine 764 (pS764) in a localized prostate cancer patient cohort and showed that nuclear enrichment of TNIK (pS764) was significantly positively correlated with ERG expression. Moreover, TNIK protein levels were dependent upon ERG expression in VCaP cells and primary cells established from a prostate cancer patient-derived xenograft. Furthermore, reduction of TNIK expression and activity by silencing TNIK expression or using the TNIK inhibitor NCB-0846 reduced cell viability, colony formation and anchorage independent growth. Therefore, TNIK represents a novel and actionable therapeutic target for ERG-positive prostate cancers that could be exploited to develop new treatments for these patients.

Li Z, Lim SK, Liang X, Lim YP
The transcriptional coactivator WBP2 primes triple-negative breast cancer cells for responses to Wnt signaling via the JNK/Jun kinase pathway.
J Biol Chem. 2018; 293(52):20014-20028 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
The transcriptional coactivator WW domain-binding protein 2 (WBP2) is an emerging oncogene and serves as a node between the signaling protein Wnt and other signaling molecules and pathways, including epidermal growth factor receptor, estrogen receptor/progesterone receptor, and the Hippo pathway. The upstream regulation of WBP2 is well-studied, but its downstream activity remains unclear. Here, we elucidated WBP2's role in triple-negative breast cancer (TNBC), in which Wnt signaling is predominantly activated. Using RNAi coupled with RNA-Seq and MS analyses to identify Wnt/WBP2- and WBP2-dependent targets in MDA-MB-231 TNBC cells, we found that WBP2 is required for the expression of a core set of genes in Wnt signaling. These included

Ren G, Shi Z, Teng C, Yao Y
Antiproliferative Activity of Combined Biochanin A and Ginsenoside Rh₂ on MDA-MB-231 and MCF-7 Human Breast Cancer Cells.
Molecules. 2018; 23(11) [PubMed] Article available free on PMC after 28/12/2019 Related Publications
Breast cancer is the most frequently diagnosed cancer in women worldwide. The antiproliferative activities of biochanin A (BA) and ginsenoside Rh₂ were determined by evaluating their inhibitory effect on MDA-MB-231 human breast cancer cell proliferation. The combination of BA with Rh₂ was also assessed. In MDA cells, combination treatment led to a decrease in the EC

Lu CH, Yeh DW, Lai CY, et al.
USP17 mediates macrophage-promoted inflammation and stemness in lung cancer cells by regulating TRAF2/TRAF3 complex formation.
Oncogene. 2018; 37(49):6327-6340 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
Macrophage accumulation and inflammation in the lung owing to stresses and diseases is a cause of lung cancer development. However, molecular mechanisms underlying the interaction between macrophages and cancer cells, which drive inflammation and stemness in cancers, are poorly understood. In this study, we investigated the expression of ubiquitin-specific peptidase 17 (USP17) in lung cancers, and role of elevated USP17 in the interaction between macrophages and lung cancer cells. USP17 expression in lung cancers was associated with poor prognosis, macrophage, and inflammatory marker expressions. Macrophages promoted USP17 expression in cancer cells. TNFR-associated factor (TRAF) 2-binding and TRAF3-binding motifs were identified in USP17, through which it interacted with and disrupted the TRAF2/TRAF3 complex. This stabilized its client proteins, enhanced inflammation and stemness in cancer cells, and promoted macrophage recruitment. In different animal studies, co-injection of macrophages with cancer cells promoted USP17 expression in tumors and tumor growth. Conversely, depletion of macrophages in host animals by clodronate liposomes reduced USP17 expression and tumor growth. In addition, overexpression of USP17 in cancer cells promoted tumor growth and inflammation-associated and stemness-associated gene expressions in tumors. These results suggested that USP17 drives a positive-feedback interaction between macrophages and cancer cells to enhance inflammation and stemness in cancer cells, and promotes lung cancer growth.

Yu C, Chen S, Guo Y, Sun C
Oncogenic TRIM31 confers gemcitabine resistance in pancreatic cancer via activating the NF-κB signaling pathway.
Theranostics. 2018; 8(12):3224-3236 [PubMed] Article available free on PMC after 28/12/2019 Related Publications

Sirinian C, Papanastasiou AD, Schizas M, et al.
RANK-c attenuates aggressive properties of ER-negative breast cancer by inhibiting NF-κB activation and EGFR signaling.
Oncogene. 2018; 37(37):5101-5114 [PubMed] Related Publications
The RANK/RANKL axis emerges as a key regulator of breast cancer initiation, progression, and metastasis. RANK-c is a RANK receptor isoform produced through alternative splicing of the TNFRSF11A (RANK) gene and a dominant-negative regulator of RANK-induced nuclear factor-κB (NF-κB) activation. Here we report that RANK-c transcript is expressed in 3.2% of cases in The Cancer Genome Atlas breast cancer cohort evenly between ER-positive and ER-negative cases. Nevertheless, the ratio of RANK to RANK-c (RANK/RANK-c) is increased in ER-negative breast cancer cell lines compared to ER-positive breast cancer cell lines. In addition, forced expression of RANK-c in ER-negative breast cancer cell lines inhibited stimuli-induced NF-κB activation and attenuated migration, invasion, colony formation, and adhesion of cancer cells. Further, RANK-c expression in MDA-MB-231 cells inhibited lung metastasis and colonization in vivo. The RANK-c-mediated inhibition of cancer cell aggressiveness and nuclear factor-κB (NF-κB) activation in breast cancer cells seems to rely on a RANK-c/TNF receptor-associated factor-2 (TRAF2) protein interaction. This was further confirmed by a mutated RANK-c that is unable to interact with TRAF2 and abolishes the ability to attenuate NF-κB activation, migration, and invasion. Additional protein interaction characterization revealed epidermal growth factor receptor (EGFR) as a novel interacting partner for RANK-c in breast cancer cells with a negative effect on EGFR phosphorylation and EGF-dependent downstream signaling pathway activation. Our findings further elucidate the complex molecular biology of the RANKL/RANK system in breast cancer and provide preliminary data for RANK-c as a possible marker for disease progression and aggressiveness.

Li Y, Huang J, Zeng B, et al.
PSMD2 regulates breast cancer cell proliferation and cell cycle progression by modulating p21 and p27 proteasomal degradation.
Cancer Lett. 2018; 430:109-122 [PubMed] Related Publications
Alterations in the ubiquitin-proteasome system (UPS) and UPS-associated proteins have been implicated in the development of many human malignancies. In this study, we investigated the expression profiles of 797 UPS-related genes using HiSeq data from The Cancer Genome Atlas and identified that PSMD2 was markedly upregulated in breast cancer. High PSMD2 expression was significantly correlated with poor prognosis. Gene set enrichment analysis revealed that transcriptome signatures involving proliferation, cell cycle, and apoptosis were critically enriched in specimens with elevated PSMD2. Consistently, PSMD2 knockdown inhibited cell proliferation and arrested cell cycle at G0/G1 phase in vitro, as well as suppressed tumor growth in vivo. Rescue assays demonstrated that the cell cycle arrest caused by silencing PSMD2 partially resulted from increased p21 and/or p27. Mechanically, PSMD2 physically interacted with p21 and p27 and mediated their ubiquitin-proteasome degradation with the cooperation of USP14. Notably, intratumor injection of therapeutic PSMD2 small interfering RNA effectively delayed xenograft tumor growth accompanied by p21 and p27 upregulation. These data provide novel insight into the role of PSMD2 in breast cancer and suggest that PSMD2 may be a potential therapeutic target.

Lezcano C, Shoushtari AN, Ariyan C, et al.
Primary and Metastatic Melanoma With NTRK Fusions.
Am J Surg Pathol. 2018; 42(8):1052-1058 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
A number of oncogenic driver mutations have been identified in melanocytic nevi and melanoma, but translocations also play a role in tumorigenesis and provide potential therapeutic targets for malignant lesions. Various translocations, such as those involving the anaplastic lymphoma kinase (ALK), neurotrophic tropomyosin receptor kinase 1 (NTRK1), and NTRK3 have been reported in spitzoid melanocytic neoplasms leading to kinase-fusion proteins that result in immunohistochemically detectable ALK or NTRK expression. We have previously reported that ALK expression can be found in nonspitzoid primary and metastatic cutaneous melanomas. In this study we report that nonspitzoid metastasizing melanomas of adults may also harbor NTRK fusions and that NTRK expression can be immunohistochemically detected in these tumors. Of 751 melanomas analyzed by next-generation sequencing, 4 metastatic melanomas were identified with NTRK fusions, 3 involving NTRK1, 1 involving NTRK2. They occurred in 3 women and 1 man. Two of the corresponding primary tumors were from the trunk, 1 from an extremity and 1 tumor arose in anal skin. One primary tumor displayed features of superficial spreading melanoma and 3 were nodular melanomas. All tumors were cytologically characterized by the presence of large epithelioid melanocytes. All tumors were immunoreactive with anti-Trk antibody. Next-generation sequencing documented that the NTRK1 fusion partners included TRIM63, DDR2, and GON4L. One tumor harbored an NTRK2-TRAF2 fusion. Thus, our findings document that NTRK kinase fusions can occur in nonspitzoid metastasizing melanomas of adults. The presence of an NTRK family fusion in these tumors may provide a therapeutic opportunity in a small subset of patients with metastatic melanoma.

Zhang W, Lu Y, Li X, et al.
CDCA3 promotes cell proliferation by activating the NF-κB/cyclin D1 signaling pathway in colorectal cancer.
Biochem Biophys Res Commun. 2018; 500(2):196-203 [PubMed] Related Publications
Cell division cycle associated 3 (CDCA3) is required for mitotic entry, and mediates the degradation of the inhibitory kinase Wee1. New evidence suggests CDCA3 plays a role in tumor promotion. However, little is known about the relevance of CDCA3 in colorectal cancer(CRC), especially in the regulation of NF-κB activity. In this study, we found that colorectal tumors significantly expressed more CDCA3 than non-cancer tissues. In addition, CDCA3 promoted CRC cell proliferation in vitro. Furthermore, downregulation of CDCA3 not only induced cell cycle arrest but also facilitated apoptosis. Mechanistically, CDCA3 activates the NF-κB signaling pathway by interacting with TRAF2 in CRC. Together, these results define a tumor-supportive role for CDCA3, which may also provide a new promising strategy for treating CRC.

Peramuhendige P, Marino S, Bishop RT, et al.
TRAF2 in osteotropic breast cancer cells enhances skeletal tumour growth and promotes osteolysis.
Sci Rep. 2018; 8(1):39 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
NFκB plays an important role in inflammation and bone remodelling. Tumour necrosis factor receptor associated factor 2 (TRAF2), a key component of NFκB signalling, has been identified as an oncogene, but its role in the regulation of breast cancer osteolytic metastasis remains unknown. Here, we report that stable overexpression of TRAF2 in parental and osteotropic sub-clones of human MDA-MB-231 (MDA-231) breast cancer cells increased cell growth and motility in vitro, whereas TRAF2 knockdown was inhibitory. In vivo, TRAF2 overexpression in the parental MDA-231-P cells enhanced tumour growth after orthotopic injection into the mammary fat pad of mice but failed to promote the metastasis of these cells to bone. In contrast, overexpression of TRAF2 in osteotropic MDA-231-BT cells increased skeletal tumour growth, enhanced osteoclast formation and worsened osteolytic bone loss after intra-tibial injection in mice. Mechanistic and functional studies in osteotropic MDA-231-BT and osteoclasts revealed that upregulation of TRAF2 increased the ability of osteotropic MDA-231-BT cells to migrate and to enhance osteoclastogenesis by a mechanism dependent, at least in part, on NFκB activation. Thus, the TRAF2/NFκB axis is implicated in the regulation of skeletal tumour burden and osteolysis associated with advanced breast cancer.

Liang J, Zhang J, Ruan J, et al.
CPNE1 Is a Useful Prognostic Marker and Is Associated with TNF Receptor-Associated Factor 2 (TRAF2) Expression in Prostate Cancer.
Med Sci Monit. 2017; 23:5504-5514 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
BACKGROUND CPNE1 plays a vital role in regulating cell differentiation. The clinical and biological values of CPNE1 in prostate cancer are still unclear. The aim of this study was to investigate the clinicopathological value of CPNE1 and the association of CPNE1 with TRAF2 expression in patients with prostate cancer. MATERIAL AND METHODS CPNE1 expression in prostate cancer was analyzed using Gene Expression Omnibus (GEO) databases. The Cancer Genome Atlas (TCGA) dataset was used to investigate the association of CPNE1 expression with TRAF2 expression in prostate cancer. The association of CPNE1 expression with recurrence-free survival in patients was also analyzed using the TCGA dataset. Immunohistochemistry assay was performed to examine CPNE1 expression in 65 normal prostate samples and 114 prostate cancer samples. The recurrence-free survival in patients was evaluated using Kaplan-Meier curves and log-rank test. In addition, multivariate and univariate analyses of prognostic factors were investigated by Cox regression. The effect of CPNE1 on TRAF2 expression was explored in human prostate cancer DU-145 cells. RESULTS Our results showed that expression level of CPNE1 is higher in prostate cancer than in normal prostate tissues (P=0.006). In the GSE35988 dataset, CPNE1 expression was found to be upregulated in castration-resistant prostate cancer compared with non-castration-resistant prostate cancer (P<0.001). Furthermore, we found that CPNE1 high expression was significantly related to tumor stage, Gleason score, and poorer biochemical recurrence-free survival in prostate cancer patients. Co-expression analysis of TCGA data showed that CPNE1 is significantly associated with TRAF2 expression. CPNE1 overexpression can upregulate TRAF2 expression in prostate cancer DU-145 cells as determined by Western blotting and immunofluorescence assays. CONCLUSIONS Overall, our findings suggest that CPNE1 is a valuable prognostic marker for evaluating recurrence-free survival and is positively related to TRAF2 expression in prostate cancer.

Basudhar D, Glynn SA, Greer M, et al.
Coexpression of NOS2 and COX2 accelerates tumor growth and reduces survival in estrogen receptor-negative breast cancer.
Proc Natl Acad Sci U S A. 2017; 114(49):13030-13035 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
Proinflammatory signaling pathways are commonly up-regulated in breast cancer. In estrogen receptor-negative (ER

Gomes-Silva D, Mukherjee M, Srinivasan M, et al.
Tonic 4-1BB Costimulation in Chimeric Antigen Receptors Impedes T Cell Survival and Is Vector-Dependent.
Cell Rep. 2017; 21(1):17-26 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
Antigen-independent tonic signaling by chimeric antigen receptors (CARs) can increase differentiation and exhaustion of T cells, limiting their potency. Incorporating 4-1BB costimulation in CARs may enable T cells to resist this functional exhaustion; however, the potential ramifications of tonic 4-1BB signaling in CAR T cells remain unclear. Here, we found that tonic CAR-derived 4-1BB signaling can produce toxicity in T cells via continuous TRAF2-dependent activation of the nuclear factor κB (NF-κB) pathway and augmented FAS-dependent cell death. This mechanism was amplified in a non-self-inactivating gammaretroviral vector through positive feedback on the long terminal repeat (LTR) promoter, further enhancing CAR expression and tonic signaling. Attenuating CAR expression by substitution with a self-inactivating lentiviral vector minimized tonic signaling and improved T cell expansion and anti-tumor function. These studies illuminate the interaction between tonic CAR signaling and the chosen expression platform and identify inhibitory properties of the 4-1BB costimulatory domain that have direct implications for rational CAR design.

Mascolo M, Romano MF, Ilardi G, et al.
Expression of FK506-binding protein 51 (FKBP51) in Mycosis fungoides.
J Eur Acad Dermatol Venereol. 2018; 32(5):735-744 [PubMed] Related Publications
BACKGROUND: Mycosis fungoides (MF) is the major subtype of cutaneous T-cell lymphomas (CTCL). It usually has a prolonged indolent clinical course with a minority of cases acquiring a more aggressive biological profile and resistance to conventional therapies, partially attributed to the persistent activation of nuclear factor-kappa B (NF-κB) pathway. In the last decade, several papers suggested an important role for the FK506-binding protein 51 (FKBP51), an immunophilin initially cloned in lymphocytes, in the control of NF-κB pathway in different types of human malignancies.
OBJECTIVES: We aimed to investigate the possible value of FKBP51 expression as a new reliable marker of outcome in patients with MF.
METHODS: We assessed by immunohistochemistry (IHC) FKBP51 expression in 44 patients with MF, representative of different stages of the disease. Immunohistochemical results were subsequently confirmed at mRNA level with quantitative PCR (qPCR) in a subset of enrolled patients. In addition, IHC and qPCR served to study the expression of some NF-κB-target genes, including the tumour necrosis factor receptor-associated factor 2 (TRAF2).
RESULTS: Our results show that FKBP51 was expressed in all evaluated cases, with the highest level of expression characterizing MFs with the worst prognosis. Moreover, a significant correlation subsisted between FKBP51 and TRAF2 IHC expression scores.
CONCLUSIONS: We hypothesize a role for FKBP51 as a prognostic marker for MF and suggest an involvement of this immunophilin in deregulated NF-κB pathway of this CTCL.

Guesmi F, Prasad S, Tyagi AK, Landoulsi A
Antinflammatory and anticancer effects of terpenes from oily fractions of Teucruim alopecurus, blocker of IκBα kinase, through downregulation of NF-κB activation, potentiation of apoptosis and suppression of NF-κB-regulated gene expression.
Biomed Pharmacother. 2017; 95:1876-1885 [PubMed] Related Publications
Teucrium alopecurus is an endemic plant limited to southern Tunisia. In the present study, the chemical composition, anticancer and nuclear factor-κB (NF-κB) inhibitory effects of Teucrium alopecurus leaf essential oil was investigated. The analysis of Teucrium alopecurus (TA-1) with Gas Chromatography-Mass Spectrometry (GC/MS) showed that α-Bisabolol, (+)-epi-Bicyclosesquiphellandrene and α-Cadinol, were found in relatively high amounts (16.16%, 15.40% and 8.52%, respectively). Cell viability was determined by 3-(4-5-dimethylthiazol-2-yl) 2-5-diphenyl-tetrazolium (MTT) assay. Cell cycle and apoptosis assay were determined by flow cytometry. TA-1 functions as an anticancer agent by triggering apoptosis potentiated by chemotherapeutic agents and TNF in human myeloid leukemia cells (KBM5) through a mechanism involving poly(ADP-ribose) polymerase (PARP) cleavage and initiator and effector caspases activation. Moreover, electrophoretic mobility shift assay (EMSA) revealed that TA-1 downregulated nuclear localization of NF-κB and its phosphorylation induced by TNF-α and this, allows the suppression of the degradation and phosphorylation of IκB and the inhibition of the phosphorylation of p65 phosphorylation and the p50-p65 heterodimer nuclear translocation, causing attenuation of NF-κB-regulated antiapoptotic (Survivin, Bcl-2, c-IAP1/2, Bcl-xL, Mcl-1, and cFLIP), invasion (ICAM1), metasatsis (MMP-9), and angiogenesis (VEGF) gene expression in KBM5; and finally reporter gene expression. Furthermore, treatment with essential oil and TNF-α suppressed the NF-κB DNA binding activity. Finally, the activation of nuclear factor-κB induced by different plasmids (TNFR1, TRADD, TRAF2, NIK, TAK1/TAB1, and IKKβ) was inhibited following treatment with TA-1. Overall, TA-1 inhibits NF-κB activation and further growth and proliferation of cancer cells.

Wei B, Liang J, Hu J, et al.
TRAF2 is a Valuable Prognostic Biomarker in Patients with Prostate Cancer.
Med Sci Monit. 2017; 23:4192-4204 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
BACKGROUND TRAF2 exerts important functions in regulating the development and progression of cancer. The aim of this study is to investigate whether TRAF2 is a valuable prognostic biomarker and to determine if it regulates TRAIL-induced apoptosis in prostate cancer. MATERIAL AND METHODS Microarray gene expression data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to determine TRAF2 expression in prostate cancer. TRAF2 expression in prostate cancer was further investigated by immunohistochemistry assay. Kaplan-Meier curves and log-rank test were used to assess the recurrence-free rate. Cox regression was used to analyze prognostic factors. Effects of TRAF2 on regulating TRAIL-induced apoptosis in DU-145 cells were further investigated. RESULTS We found that TRAF2 was significantly upregulated in prostate cancer compared with normal prostate samples (P<0.001). In addition, compared with primary prostate cancer, TRAF2 was upregulated in metastatic prostate cancer (P=0.006). Furthermore, our results showed that high expression of TRAF2 was significantly associated with tumor stage of prostate cancer (P=0.035). TRAF2 high expression was associated with poorer recurrence-free survival in prostate cancer patients (P=0.013). TRAF2 was found to be a valuable independent prognostic factor for predicting recurrence-free survival (P=0.026). In addition, the present results indicate that TRAF2 affects TRAIL-induced apoptosis in prostate cancer DU-145 cells via regulating cleaved Caspase-8 and c-Flip expression. CONCLUSIONS TRAF2 could be a novel prognostic biomarker for predicting recurrence-free survival in patients with prostate cancer, which might be associated with the effects of TRAF2 in regulating TRAIL-induced apoptosis in prostate cancer cells via c-Flip/Caspase-8 signalling.

Paiva C, Rowland TA, Sreekantham B, et al.
SYK inhibition thwarts the BAFF - B-cell receptor crosstalk and thereby antagonizes Mcl-1 in chronic lymphocytic leukemia.
Haematologica. 2017; 102(11):1890-1900 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
Although small molecule inhibitors of B-cell receptor-associated kinases have revolutionized therapy in chronic lymphocytic leukemia (CLL), responses are incomplete. Pro-survival signaling emanating from the microenvironment may foster therapeutic resistance of the malignant B cells resident in the protective lymphoid niches. B-cell activating factor (BAFF) is critical to the survival of both healthy and neoplastic B cells. However, the pro-survival pathways triggered by BAFF have not been fully characterized. Here we show that BAFF elicited resistance to spontaneous and drug-induced apoptosis in stromal co-cultures, induced activation of both canonical and non-canonical NFκB signaling pathways, and triggered B-cell receptor signaling in CLL cells, independently of

Wei B, Ruan J, Mi Y, et al.
Knockdown of TNF receptor-associated factor 2 (TRAF2) modulates in vitro growth of TRAIL-treated prostate cancer cells.
Biomed Pharmacother. 2017; 93:462-469 [PubMed] Related Publications
TNF receptor-associated factor 2 (TRAF2) is documented to regulate tumor development and progression. Currently, the effect of TRAF2 on growth of androgen-refractory prostate cancer in response to TRAIL and the molecular mechanisms are not well understood. Here, we aim to investigate the effect of TRAF2 on in vitro growth of human androgen-insensitive prostate cancer DU-145 cells in the presence of TRAIL. Bioinformatics analysis of the Cancer Genome Atlas (TCGA) data was performed to examine TRAF2 expression and the prognostic value in prostate cancer. Microarray data of GSE21032 dataset were downloaded from Gene Expression Omnibus (GEO) to explore TRAF2 expression in metastatic prostate cancer. Bioinformatics analysis was further conducted to investigate the association of TRAF2 expression with recurrence-free survival in prostate cancer patients. Colony formation, cell viability, and Annexin V/PI apoptosis assays were performed to investigate the effect of TRAF2 on in vitro growth and apoptosis in TRAIL-treated DU-145 cells. The expression levels of mRNA and protein were detected by quantitative RT-PCR and immunoblotting assays. Bioinformatics analysis indicated that TRAF2 expression is significantly upregulated in prostate cancer patients with high Gleason scores (GS>7) compared with those with low Gleason scores (GS≤7). Upregulation of TRAF2 expression is significantly associated with recurrence-free survival in patients. In addition, TRAF2 knockdown can enhance apoptosis and downregulate SIRT1 expression in TRAIL-treated DU-145 cells. In vitro experiments further showed that SIRT1 knockdown can inhibit growth, and promote apoptosis in TRAIL-treated DU-145 cells. Overall, TRAF2 can influence in vitro growth of TRAIL-treated DU-145 cells at least partially via regulating SIRT1 expression, and may be a potentially valuable biomarker predicting recurrence-free survival in prostate cancer patients.

Liu H, Ma Y, He HW, et al.
SPHK1 (sphingosine kinase 1) induces epithelial-mesenchymal transition by promoting the autophagy-linked lysosomal degradation of CDH1/E-cadherin in hepatoma cells.
Autophagy. 2017; 13(5):900-913 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
SPHK1 (sphingosine kinase 1), a regulator of sphingolipid metabolites, plays a causal role in the development of hepatocellular carcinoma (HCC) through augmenting HCC invasion and metastasis. However, the mechanism by which SPHK1 signaling promotes invasion and metastasis in HCC remains to be clarified. Here, we reported that SPHK1 induced the epithelial-mesenchymal transition (EMT) by accelerating CDH1/E-cadherin lysosomal degradation and facilitating the invasion and metastasis of HepG2 cells. Initially, we found that SPHK1 promoted cell migration and invasion and induced the EMT process through decreasing the expression of CDH1, which is an epithelial marker. Furthermore, SPHK1 accelerated the lysosomal degradation of CDH1 to induce EMT, which depended on TRAF2 (TNF receptor associated factor 2)-mediated macroautophagy/autophagy activation. In addition, the inhibition of autophagy recovered CDH1 expression and reduced cell migration and invasion through delaying the degradation of CDH1 in SPHK1-overexpressing cells. Moreover, the overexpression of SPHK1 produced intracellular sphingosine-1-phosphate (S1P). In response to S1P stimulation, TRAF2 bound to BECN1/Beclin 1 and catalyzed the lysine 63-linked ubiquitination of BECN1 for triggering autophagy. The deletion of the RING domain of TRAF2 inhibited autophagy and the interaction of BECN1 and TRAF2. Our findings define a novel mechanism responsible for the regulation of the EMT via SPHK1-TRAF2-BECN1-CDH1 signal cascades in HCC cells. Our work indicates that the blockage of SPHK1 activity to attenuate autophagy may be a promising strategy for the prevention and treatment of HCC.

Oh YT, Yue P, Sun SY
DR5 suppression induces sphingosine-1-phosphate-dependent TRAF2 polyubiquitination, leading to activation of JNK/AP-1 and promotion of cancer cell invasion.
Cell Commun Signal. 2017; 15(1):18 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
BACKGROUND: Death receptor (DR5), a well-characterized death domain-containing cell surface pro-apoptotic protein, has been suggested to suppress cancer cell invasion and metastasis. However, the underlying mechanisms have not been fully elucidated. Our recent work demonstrates that DR5 suppression promotes cancer cell invasion and metastasis through caspase-8/TRAF2-mediated activation of ERK and JNK signaling and MMP1 elevation. The current study aimed at addressing the mechanism through which TRAF2 is activated in a caspase-8 dependent manner.
RESULTS: DR5 knockdown increased TRAF2 polyubiquitination, a critical event for TRAF2-mediated JNK/AP-1 activation. Suppression of sphingosine-1-phosphate (S1P) generation or depletion of casapse-8 inhibited not only enhancement of cell invasion, but also elevation and polyubiquitination of TRAF2, activation of JNK/AP-1 activation and increased expression of MMP1 induced by DR5 knockdown.
CONCLUSIONS: Both S1P and caspase-8 are critical for TRAF2 stabilization, polyubiquitination, subsequent activation of JNK/AP1 signaling and MMP1 expression and final promotion of cell invasion.

Zhao J, Li H, Min L, et al.
High expression of tumor necrosis factor receptor-associated factor 2 promotes tumor metastasis and is associated with unfavorable prognosis in gastric cancer.
J Gastroenterol Hepatol. 2018; 33(2):431-442 [PubMed] Related Publications
BACKGROUND: Tumor necrosis factor receptor-associated factor 2 (TRAF2) is a key effector in the activation of nuclear factor kappa B (NF-κB). Nevertheless, the role of TRAF2 in gastric tumorigenesis remains little defined.
METHODS: Immunohistochemistry was used to find the relationship between TRAF2 expression and clinicopathological characteristics of gastric cancer patients, and nomogram was applied to predict the overall survival of patients. Besides, we performed transwell assays to detect the function of TRAF2 in promoting metastasis and explored the correlations between TRAF2, NF-κB, and interleukin-8 (IL-8) in vitro. In addition, we examined the correlation between TRAF2 and tumor microenvironment by immunohistochemistry staining.
RESULTS: In our study, we found that TRAF2 expression was markedly increased in gastric cancer tissues. High intratumoral TRAF2 staining, which was associated with tumor invasion and metastasis, was also an independent poor prognosticator for gastric cancer patients. In vitro studies revealed that TRAF2 enhanced NF-κB activation and subsequent IL-8 expression in gastric cancer cells. Inhibition of NF-κB or IL-8 signaling attenuated TRAF2-induced migration and invasion abilities. High TRAF2 expression was confirmed to be associated with both high intratumoral and serum levels of IL-8. In addition, TRAF2 expression was positively correlated with neutrophil and macrophage infiltration as well as microvessels formation in gastric cancer samples.
CONCLUSIONS: These results suggest that TRAF2 functions as an important modulator in tumor metastasis and tumor microenvironment formation and is a novel independent prognostic factor of gastric cancer.

Özata DM, Li X, Lee L, et al.
Loss of miR-514a-3p regulation of PEG3 activates the NF-kappa B pathway in human testicular germ cell tumors.
Cell Death Dis. 2017; 8(5):e2759 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
Deregulation of microRNAs (miRNAs) contributes to the development and progression of many cancer types; however, their functions in the pathogenesis of testicular germ cell tumor (TGCT) remain unclear. Here, we determined miRNA expression profiles of TGCTs and normal testes using small RNA sequencing, and identified several deregulated miRNAs in TGCTs, including the miR-506~514 cluster. In functional studies in vitro we demonstrated that miR-514a-3p induced apoptosis through direct regulation of the paternally expressed gene 3 (PEG3), and ectopically expressed PEG3 could rescue the apoptotic effect of miR-514a-3p overexpression. Silencing of PEG3 or miR-514a-3p overexpression reduced nuclear accumulation of p50 and NF-κB reporter activity. Furthermore, PEG3 was co-immunoprecipitated with tumor necrosis factor receptor-associated factor 2 (TRAF2) in TGCT cell lysates. We propose a model of PEG3-mediated activation of NF-κB in TGCT. Loss of miR-514a-3p expression in TGCT increases PEG3 expression that recruits TRAF2 and activates the NF-kappa B pathway, which protects germ cells from apoptosis. Importantly, we observed strong expression of PEG3 and nuclear p50 in the majority of TGCTs (83% and 78%, respectively). In conclusion, our study describes a novel function for miR-514a-3p in TGCT and highlights an unrecognized mechanism of PEG3 regulation and NF-κB activation in TGCT.

Lee Y, Jung JI, Park KY, et al.
Synergistic inhibition effect of TNIK inhibitor KY-05009 and receptor tyrosine kinase inhibitor dovitinib on IL-6-induced proliferation and Wnt signaling pathway in human multiple myeloma cells.
Oncotarget. 2017; 8(25):41091-41101 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
Multiple myeloma is a fetal form of plasma cell malignancy characterized by abnormal clonal proliferation of plasma cells. Especially, the canonical Wnt signaling pathway mediated by β-catenin is activated in multiple myeloma cells, stimulating their proliferation. Here, we investigated the relationship between interleukin-6-induced proliferation of multiple myeloma cells and Traf2- and Nck-interacting kinase (TNIK) expression in Wnt signaling. Interleukin-6 increased the proliferation of multiple myeloma cells and TNIK mRNA and protein expression. In addition, we examined the effect on TNIK of TNIK inhibitor KY-05009 and receptor tyrosine kinase inhibitor dovitinib and whether inhibition of TNIK suppresses the interleukin-6-induced proliferation of multiple myeloma cells. KY-05009 and dovitinib synergistically inhibited interleukin-6-stimulated proliferation and induced apoptosis through the inhibition of Wnt signaling in MM cells. Our results provide crucial information that TNIK is involved in the interleukin-6-dependent proliferation of multiple myeloma cells and inhibition of Wnt signaling involving TNIK could be a therapeutic strategy for the treatment of interleukin-6-dependent multiple myeloma.

Rohban MH, Singh S, Wu X, et al.
Systematic morphological profiling of human gene and allele function via Cell Painting.
Elife. 2017; 6 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
We hypothesized that human genes and disease-associated alleles might be systematically functionally annotated using morphological profiling of cDNA constructs, via a microscopy-based Cell Painting assay. Indeed, 50% of the 220 tested genes yielded detectable morphological profiles, which grouped into biologically meaningful gene clusters consistent with known functional annotation (e.g., the RAS-RAF-MEK-ERK cascade). We used novel subpopulation-based visualization methods to interpret the morphological changes for specific clusters. This unbiased morphologic map of gene function revealed TRAF2/c-REL negative regulation of YAP1/WWTR1-responsive pathways. We confirmed this discovery of functional connectivity between the NF-κB pathway and Hippo pathway effectors at the transcriptional level, thereby expanding knowledge of these two signaling pathways that critically regulate tumor initiation and progression. We make the images and raw data publicly available, providing an initial morphological map of major biological pathways for future study.

Gade TPF, Tucker E, Nakazawa MS, et al.
Ischemia Induces Quiescence and Autophagy Dependence in Hepatocellular Carcinoma.
Radiology. 2017; 283(3):702-710 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
Purpose To characterize hepatocellular carcinoma (HCC) cells surviving ischemia with respect to cell cycle kinetics, chemosensitivity, and molecular dependencies that may be exploited to potentiate treatment with transarterial embolization (TAE). Materials and Methods Animal studies were performed according to institutionally approved protocols. The growth kinetics of HCC cells were studied in standard and ischemic conditions. Viability and cell cycle kinetics were measured by using flow cytometry. Cytotoxicity profiling was performed by using a colorimetric cell proliferation assay. Analyses of the Cancer Genome Atlas HCC RNA-sequencing data were performed by using Ingenuity Pathway Analysis software. Activation of molecular mediators of autophagy was measured with Western blot analysis and fluorescence microscopy. In vivo TAE was performed in a rat model of HCC with (n = 5) and without (n = 5) the autophagy inhibitor Lys05. Statistical analyses were performed by using GraphPad software. Results HCC cells survived ischemia with an up to 43% increase in the fraction of quiescent cells as compared with cells grown in standard conditions (P < .004). Neither doxorubicin nor mitomycin C potentiated the cytotoxic effects of ischemia. Gene-set analysis revealed an increase in mRNA expression of the mediators of autophagy (eg, CDKN2A, PPP2R2C, and TRAF2) in HCC as compared with normal liver. Cells surviving ischemia were autophagy dependent. Combination therapy coupling autophagy inhibition and TAE in a rat model of HCC resulted in a 21% increase in tumor necrosis compared with TAE alone (P = .044). Conclusion Ischemia induces quiescence in surviving HCC cells, resulting in a dependence on autophagy, providing a potential therapeutic target for combination therapy with TAE.

Yamada T, Masuda M
Emergence of TNIK inhibitors in cancer therapeutics.
Cancer Sci. 2017; 108(5):818-823 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
The outcome of patients with metastatic colorectal cancer remains unsatisfactory. To improve patient prognosis, it will be necessary to identify new drug targets based on molecules that are essential for colorectal carcinogenesis, and to develop therapeutics that target such molecules. The great majority of colorectal cancers (>90%) have mutations in at least one Wnt signaling pathway gene. Aberrant activation of Wnt signaling is a major force driving colorectal carcinogenesis. Several therapeutics targeting Wnt pathway molecules, including porcupine, frizzled receptors and tankyrases, have been developed, but none of them have yet been incorporated into clinical practice. Wnt signaling is most frequently activated by loss of function of the adenomatous polyposis coli (APC) tumor suppressor gene. Restoration of APC gene function does not seem to be a realistic therapeutic approach, and, therefore, only Wnt signaling molecules downstream of the APC gene product can be considered as targets for pharmacological intervention. Traf2 and Nck-interacting protein kinase (TNIK) was identified as a regulatory component of the β-catenin and T-cell factor-4 (TCF-4) transcriptional complex. Several small-molecule compounds targeting this protein kinase have been shown to have anti-tumor effects against various cancers. An anthelmintic agent, mebendazole, was recently identified as a selective inhibitor of TNIK and is under clinical evaluation. TNIK regulates Wnt signaling in the most downstream part of the pathway, and its pharmacological inhibition seems to be a promising therapeutic approach. We demonstrated the feasibility of this approach by developing a small-molecule TNIK inhibitor, NCB-0846.

Xu PP, Zhong HJ, Huang YH, et al.
B-cell Function Gene Mutations in Diffuse Large B-cell Lymphoma: A Retrospective Cohort Study.
EBioMedicine. 2017; 16:106-114 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous subtype of non-Hodgkin lymphoma. In addition to clinical and immunophenotypic characteristics, recurrent gene mutations have recently been identified in patients with DLBCL using next-generation sequencing technologies. The aim of this study is to investigate the clinical relevance of B-cell function gene mutations in DLBCL. Clinical analysis was performed on 680 Chinese DLBCL patients (146 non-CR and 534 CR cases) treated with six cycles of 21-day R-CHOP (Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), alone or followed by two additional doses of rituximab consolidation on patients' own intention. Somatic mutations of B-cell function genes were further screened on 275 (71 non-CR and 204 CR) cases with available tumor samples by targeted sequencing, including genes involved in B-cell receptors (BCRs) pathway (CARD11, LYN, CD79A, and CD79B), Toll-like receptors (TLRs) pathway (MYD88), and tumor necrotic factor receptor (TNFR) pathway (TRAF2 and TNFAIP3). B-cell function gene mutations occurred in 44.0% (121/275) of DLBCL patients. The TLRs and TNFR related gene mutations were more frequently observed in non-CR patients (p=0.019 and p=0.032, respectively). BCRs related gene mutations, as well as revised IPI (R-IPI) and double BCL-2/MYC expression, were independently related to short progression-free survival in DLBCL after CR. The adverse prognostic effect of BCRs related gene mutations could be overcome by two additional doses of rituximab consolidation. These results highlight the molecular heterogeneity of DLBCL and identify a significant role of B-cell function gene mutations on lymphoma progression and response to rituximab in DLBCL.

Riether C, Schürch CM, Bührer ED, et al.
CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia.
J Exp Med. 2017; 214(2):359-380 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
Aberrant proliferation, symmetric self-renewal, increased survival, and defective differentiation of malignant blasts are key oncogenic drivers in acute myeloid leukemia (AML). Stem cell gene signatures predict poor prognosis in AML patients; however, with few exceptions, these deregulated molecular pathways cannot be targeted therapeutically. In this study, we demonstrate that the TNF superfamily ligand-receptor pair CD70/CD27 is expressed on AML blasts and AML stem/progenitor cells. CD70/CD27 signaling in AML cells activates stem cell gene expression programs, including the Wnt pathway, and promotes symmetric cell divisions and proliferation. Soluble CD27, reflecting the extent of CD70/CD27 interactions in vivo, was significantly elevated in the sera of newly diagnosed AML patients and is a strong independent negative prognostic biomarker for overall survival. Blocking the CD70/CD27 interaction by mAb induced asymmetric cell divisions and differentiation in AML blasts and AML stem/progenitor cells, inhibited cell growth and colony formation, and significantly prolonged survival in murine AML xenografts. Importantly, hematopoietic stem/progenitor cells from healthy BM donors express neither CD70 nor CD27 and were unaffected by blocking mAb treatment. Therefore, targeting CD70/CD27 signaling represents a promising therapeutic strategy for AML.

Zhou Y, Lin S, Tseng KF, et al.
Selumetinib suppresses cell proliferation, migration and trigger apoptosis, G1 arrest in triple-negative breast cancer cells.
BMC Cancer. 2016; 16(1):818 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
BACKGROUND: Triple-negative breast cancer (TNBC) has aggressive progression with poor prognosis and ineffective treatments. Selumetinib is an allosteric, ATP-noncompetitive inhibitor of MEK1/2, which has benn known as effective antineoplastic drugs for several malignant tumors. We hypothesized that Selumetinib might be potential drug for TNBC and explore the mechanism.
METHODS: After treated with Selumetinib, the viability and mobility of HCC1937 and MDA-MB-231 were detected by MTT, tunnel, wound-healing assay, transwell assay and FCM methods. MiR array was used to analysis the change of miRs. We predicted and verified CUL1 is the target of miR-302a using Luciferase reporter assay. We also silenced the CUL1 by siRNA, to clarify whether CUL1 take part in the cell proliferation, migration and regulated its substrate TIMP1 and TRAF2. Moreover, after transfection, the antagomir of miR-302a and CUL1 over-expressed plasmid into HCC1937 and MDA-MB-231 cell accompanied with the Selumetinib treatment, we detected the proliferation and migration again.
RESULTS: Selumetinib reduce the proliferation, migration, triggered apoptosis and G1 arrest in TNBC cell lines. In this process, the miR-302a was up-regulated and inhibited the CUL1 expression. The later negatively regulated the TIMP1 and TRAF2. As soon as we knockdown miR-302a and over-expression CUL1 in TNBC cells, the cytotoxicity of Selumetinib was reversed.
CONCLUSIONS: MiR-302a targeted regulated the CUL1 expression and mediated the Selumetinib-induced cytotoxicity of triple-negative breast cancer.

Yang C, Wang H, Zhang B, et al.
LCL161 increases paclitaxel-induced apoptosis by degrading cIAP1 and cIAP2 in NSCLC.
J Exp Clin Cancer Res. 2016; 35(1):158 [PubMed] Article available free on PMC after 28/12/2019 Related Publications
BACKGROUND: LCL161, a novel Smac mimetic, is known to have anti-tumor activity and improve chemosensitivity in various cancers. However, the function and mechanisms of the combination of LCL161 and paclitaxel in non-small cell lung cancer (NSCLC) remain unknown.
METHODS: Cellular inhibitor of apoptotic protein 1 and 2 (cIAP1&2) expression in NSCLC tissues and adjacent non-tumor tissues were assessed by immunohistochemistry. The correlations between cIAP1&2 expression and clinicopathological characteristics, prognosis were analyzed. Cell viability and apoptosis were measured by MTT assays and Flow cytometry. Western blot and co-immunoprecipitation assay were performed to measure the protein expression and interaction in NF-kB pathway. siRNA-mediated gene silencing and caspases activity assays were applied to demonstrate the role and mechanisms of cIAP1&2 and RIP1 in lung cancer cell apoptosis. Mouse xenograft NSCLC models were used in vivo to determine the therapeutic efficacy of LCL161 alone or in combination with paclitaxel.
RESULTS: The expression of cIAP1 and cIAP2 in Non-small cell lung cancer (NSCLC) tumors was significantly higher than that in adjacent normal tissues. cIAP1 was highly expressed in patients with late TNM stage NSCLC and a poor prognosis. Positivity for both cIAP1 and cIAP2 was an independent prognostic factor that indicated a poorer prognosis in NSCLC patients. LCL161, an IAP inhibitor, cooperated with paclitaxel to reduce cell viability and induce apoptosis in NSCLC cells. Molecular studies revealed that paclitaxel increased TNFα expression, thereby leading to the recruitment of various factors and the formation of the TRADD-TRAF2-RIP1-cIAP complex. LCL161 degraded cIAP1&2 and released RIP1 from the complex. Subsequently, RIP1 was stabilized and bound to caspase-8 and FADD, thereby forming the caspase-8/RIP1/FADD complex, which activated caspase-8, caspase-3 and ultimately lead to apoptosis. In nude mouse xenograft experiments, the combination of LCL161 and paclitaxel degraded cIAP1,2, activated caspase-3 and inhibited tumor growth with few toxic effects.
CONCLUSION: Thus, LCL161 could be a useful agent for the treatment of NSCLC in combination with paclitaxel.

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