RELB

Gene Summary

Gene:RELB; RELB proto-oncogene, NF-kB subunit
Aliases: IREL, I-REL, IMD53, REL-B
Location:19q13.32
Summary:-
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transcription factor RelB
Source:NCBIAccessed: 30 August, 2019

Ontology:

What does this gene/protein do?
Show (12)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 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.

  • Transcription Factor RelA
  • Prostate Cancer
  • Messenger RNA
  • Apoptosis
  • Cell Survival
  • RTPCR
  • Promoter Regions
  • siRNA
  • Cancer Gene Expression Regulation
  • Signal Transduction
  • Cell Line
  • NF-kappa B p52 Subunit
  • Neoplasm Proteins
  • Gene Expression Regulation
  • Cell Proliferation
  • Virus Replication
  • p53 Protein
  • Proto-Oncogene Proteins c-rel
  • Proto-Oncogene Proteins
  • DNA-Binding Proteins
  • Vertebrates
  • Breast Cancer
  • I-kappa B Kinase
  • Cell Nucleus
  • Transcription Factors
  • NF-kappa B
  • Protein Binding
  • Vascular Cell Adhesion Molecule-1
  • Cell Movement
  • Gene Expression Profiling
  • BCL2 protein
  • RNA Interference
  • Drug Resistance
  • Transcription
  • Transcription Factor RelB
  • Chromosome 19
  • Proto-Oncogenes
  • Hodgkin Lymphoma
  • rac1 GTP-Binding Protein
  • beta Catenin
Tag cloud generated 30 August, 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: RELB (cancer-related)

Gamboa-Cedeño AM, Castillo M, Xiao W, et al.
Alternative and canonical NF-kB pathways DNA-binding hierarchies networks define Hodgkin lymphoma and Non-Hodgkin diffuse large B Cell lymphoma respectively.
J Cancer Res Clin Oncol. 2019; 145(6):1437-1448 [PubMed] Related Publications
PURPOSE: Despite considerable evidence that supports the NF-kB role in the immune system and lymphomagenesis, it is unclear whether specific NF-kB dimers control a particular set of genes that account for their biological functions. Our previous work showed that Hodgkin Lymphoma (HL) is unique, among germinal center (GC)-derived lymphomas, with respect to its dependency on Rel-B to survive. In contrast, diffuse large B-Cell lymphoma (DLBCL) including both Activated B-Cell-Like and Germinal Center B-Cell-Like, requires cREL and Rel-A to survive and it is not affected by Rel-B depletion. These findings highlighted the activity of specific NF-kB subunits in different GC-derived lymphomas.
METHODS: Sequenced chromatin immunoprecipitated DNA fragments (ChIP-Seq) analysis revealed an extensive NF-kB DNA-binding network in DLBCL and HL. The ChIP-Seq data was merged with microarray analysis following the Rel-A, Rel-B or cRel knockdown to determine effectively regulated genes.
RESULTS: Downstream target analysis showed enrichment for cell cycle control, among other signatures. Rel-B and cRel controlled different genes within the same signature in HL and DLBCL, respectively. BCL2 was exclusively controlled by Rel-B in HL. Both mRNA and protein levels decreased following Rel-B depletion meanwhile there was no change upon cRel knock-down. BCL2 exogenous expression partially rescued the death induced by decreased Rel-B in HL cells.
CONCLUSION: The Rel-B hierarchical network defined HL and the cRel hierarchical network characterized DLBCL. Each Rel member performs specific functions in distinct GC-derived lymphomas. This result should be considered for the development of targeted therapies that are aimed to selectively inhibit individual NF-kB dimers.

Das R, Coupar J, Clavijo PE, et al.
Lymphotoxin-β receptor-NIK signaling induces alternative RELB/NF-κB2 activation to promote metastatic gene expression and cell migration in head and neck cancer.
Mol Carcinog. 2019; 58(3):411-425 [PubMed] Related Publications
Head and neck squamous cell carcinomas (HNSCC) preferentially spread to regional cervical tissues and lymph nodes. Here, we hypothesized that lymphotoxin-β (LTβ), receptor LTβR, and NF-κB-inducing kinase (NIK), promote the aberrant activation of alternative NF-κB2/RELB pathway and genes, that enhance migration and invasion of HNSCC. Genomic and expression alterations of the alternative NF-kB pathway were examined in 279 HNSCC tumors from The Cancer Genome Atlas (TCGA) and a panel of HNSCC lines. LTβR is amplified or overexpressed in HNSCC of the larynx or oral cavity, while LTβ, NIK, and RELB are overexpressed in cancers arising within lymphoid oropharyngeal and tonsillar sites. Similarly, subsets of HNSCC lines displayed overexpression of LTβR, NIK, and RELB proteins. Recombinant LTβ, and siRNA depletion of endogenous LTβR and NIK, modulated expression of LTβR, NIK, and nuclear translocation of NF-κB2(p52)/RELB as well as functional NF-κB promoter reporter activity. Treatment with a NIK inhibitor (1,3[2H,4H]-Iso-Quinoline Dione) reduced the protein expression of NIK and NF-κB2(p52)/RELB, and blocked LTβ induced nuclear translocation of RELB. NIK and RELB siRNA knockdown or NIK inhibitor slowed HNSCC migration or invation in vitro. LTβ-induces expression of migration and metastasis related genes, including hepatocyte growth/scatter factor receptor MET. Knockdown of NIK or MET similarly inhibited the migration of HNSCC cell lines. This may help explain why HNSCC preferentially migrate to local lymph nodes, where LTβ is expressed. Our findings show that LTβ/LTβR promotes activation of the alternative NIK-NF-κB2/RELB pathway to enhance MET-mediated cell migration in HNSCC, which could be potential therapeutic targets in HNSCC.

Juskevicius D, Jucker D, Dietsche T, et al.
Novel cell enrichment technique for robust genetic analysis of archival classical Hodgkin lymphoma tissues.
Lab Invest. 2018; 98(11):1487-1499 [PubMed] Related Publications
Approximately 15% of patients with classical Hodgkin lymphoma (cHL) die after relapse or progressive disease. Comprehensive genetic characterization is required to better understand its molecular pathology and improve management. However, genetic information on cHL is hard to obtain mainly due to rare malignant Hodgkin- and Reed-Sternberg cells (HRSC), whose overall frequencies in the affected tissues ranges from 0.1 to 10%. Therefore, enrichment of neoplastic cells is necessary for the majority of genetic investigations. We have developed a new high-throughput method for marker-based enrichment of archival formalin-fixed and paraffin-embedded (FFPE) tissue-derived HRSC nuclei by fluorescence-assisted flow sorting (FACS) and successfully applied it on ten cHL cases. Genomic DNA extracted from sorted nuclei was used for targeted high-throughput sequencing (HTS) of 68 genes that are frequently affected in lymphomas. Chromosomal copy number aberrations were investigated by the Agilent SurePrint 180k microarray. Our method enabled HRSC nuclei enrichment to 40-90% in sorted populations. This level of enrichment was sufficient for reliable identification of tumor-specific mutations and copy number aberrations. Genetic analysis revealed that components of JAK-STAT signaling pathway were affected in all investigated tumors by frequent mutations of SOCS1 and STAT6 as well as copy number gains of JAK2. Involvement of nuclear factor-κB (NF-κB) pathway compounds was evident from recurrent gains of the locus containing the REL gene and mutations in TNFAIP3 and CARD11. Finally, genetic alterations of PD-L1 and B2M suggested immune evasion as mechanisms of oncogenesis in some patients. In this work, we present a new method for HRSC enrichment from FFPE tissue blocks by FACS and demonstrate the feasibility of a wide-scale genetic analysis by cutting-edge molecular methods. Our work opens the door to a large resource of archived clinical cHL samples and lays foundation to more complex studies aimed to answer important biological and clinical questions that are critical to improve cHL management.

Zhang Y, Xu Z, Ding J, et al.
HZ08 suppresses RelB-activated MnSOD expression and enhances Radiosensitivity of prostate Cancer cells.
J Exp Clin Cancer Res. 2018; 37(1):174 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The development of radioresistance is one of main causes for therapeutic failure of prostate cancer (PCa). The present study aims to investigate the function and the related mechanism by which HZ08 sensitizes radiotherapeutic efficiency to treat aggressive PCa cells.
METHODS: PCa cells were pretreated with HZ08 (6,7-dimethoxy-1-(3,4-dimethoxy) benzyl-2-(N-n-octyl-N'-cyano) guanyl-1,2,3,4-tetrahydroisoquinoline) and followed by ionizing radiation (IR) treatment. Cytotoxicity in the treated cells was analyzed to assess the radiosensitization capacity of HZ08 by flow cytometry, MTT and colony survival assays. The cellular levels of reactive oxygen species (ROS) and oxygen consumption rates (OCR) were measured using specific ROS detection probes and a Seahorse XF96 Analyzer, respectively. RelB binding to the NF-κB intronic enhancer region of the human SOD2 gene was determined using a ChIP assay. The levels of phosphorylation of PI3K, Akt and IKKα were quantified and further confirmed using a PI3K inhibitor. Finally, the synergistic effect of HZ08 on radiosensitization of PCa cells was validated using a mouse xenograft tumor model.
RESULTS: HZ08 enhanced radiosensitivity of PCa cells through increasing ROS and declining mitochondrial respiration due to suppression of mitochondrial antioxidant enzyme MnSOD. Mechanistically, HZ08 appeared to inhibit PI3K/Akt/IKKα signaling axis, resulting in transcriptional repression of MnSOD expression by preventing RelB nuclear translocation.
CONCLUSIONS: HZ08 can serve as a useful radiosensitizing agent to improve radiotherapy for treating aggressive PCa cells with high level of constitutive RelB. The present study suggests a promising approach for enhancing radiotherapeutic efficiency to treat advanced PCa by inhibiting antioxidant defense function.

Jiang XF, Ding L, Tian Y, et al.
Interaction of STAT3 and RelB modulates MMP-1 in colon cancer.
Chem Biol Interact. 2018; 293:94-99 [PubMed] Related Publications
BACKGROUND: MMP-1 (Matrix metalloproteinase-1) promotes carcinogenesis and distant metastasis in different cancers. Regulation of MMP-1 could occur at multiple levels: epigenetically, post-transcriptionally, or post-translationally. An increasing body of evidence supports that the cytoplasmic transcription factor STAT3 (signal transducer and activator of transcription 3) is activated constitutively in a variety of cancers wherein it significantly affects the growth of tumors and also facilitates metastasis. In addition, STAT3 has been found to regulate nuclear activity pro-inflammatory transcriptional factor, NF-κB signaling, especially, the alternative one (RelB/p100) by directly interacting with them METHOD AND RESULTS: In this proof of concept study, we tested the hypothesis that STAT3 interacts with RelB to promote tumor invasion by positively regulating MMP-1 in colon cancer. We found that RelB and STAT3 were constitutively localized in the nucleus of colon cancer in surgically-resected specimens with use of Western blot analysis, which was further confirmed by immunofluorescence (IF) staining in colon carcinoma cell line HT29. We further observed that STAT3/RelB knockdown resulted in reduced MMP-1. Our results from chromatin immunoprecipitation studies further established that association between RelB and MMP-1 promoter decreased when STAT3 was depleted, and conversely, STAT3 association with MMP-1 decreased with the knockdown of RelB.
CONCLUSION: These results suggest that STAT3 and ReB constitute a minimal activator complex for positive regulation of MMP-1 in colon cancer.

Tao Y, Liu Z, Hou Y, et al.
Alternative NF-κB signaling promotes colorectal tumorigenesis through transcriptionally upregulating Bcl-3.
Oncogene. 2018; 37(44):5887-5900 [PubMed] Related Publications
Multiple studies have shown that chronic inflammation is closely related to the occurrence and development of colorectal cancer (CRC). Classical NF-κB signaling, the key factor in controlling inflammation, has been found to be of great importance to CRC development. However, the role of alternative NF-κB signaling in CRC is still elusive. Here, we found aberrant constitutive activation of alternative NF-κB signaling both in CRC tissue and CRC cells. Knockdown of RelB downregulates c-Myc and upregulates p27

So D, Shin HW, Kim J, et al.
Cervical cancer is addicted to SIRT1 disarming the AIM2 antiviral defense.
Oncogene. 2018; 37(38):5191-5204 [PubMed] Related Publications
Mammalian cells are equipped with antiviral innate immunity. To survive and grow, human papilloma virus (HPV)-infected cervical cancer cells must overcome this host defense system. However, the precise mechanism whereby cervical cancer cells evade the immunity is not fully understood. We noted that Sirtuin 1 (SIRT1) is overexpressed in HPV-infected cervical cancer cells and hypothesized that SIRT1 counteracts antiviral immunity. Here, we found that cervical cancer cells undergo massive death by SIRT1 knockdown, but this effect is reversed by SIRT1 restoration. SIRT1-knocked-down cells showed representative features of pyroptosis, as well as highly expressed absent in melanoma 2 (AIM2) and its downstream genes related to the inflammasome response. Mechanistically, SIRT1 repressed the NF-κB-driven transcription of the AIM2 gene by destabilizing the RELB mRNA. Interestingly, pyroptotic death signaling in SIRT1-knocked-down cells was transmitted to naïve cervical cancer cells, which was mediated by extracellular vesicles carrying AIM2 inflammasome proteins. Furthermore, the growth of cervical cancer xenografts was significantly inhibited by either SIRT1-targeting siRNAs or SIRT1-knockdown-derived extracellular vesicles. Immunohistochemical analyses showed that SIRT1 expression correlated with poor clinical outcomes in cervical cancer. In conclusion, SIRT1 enabled HPV-infected cervical cancer cells to continue growing by nullifying AIM2 inflammasome-mediated immunity. Without SIRT1, cervical cancer cells could no longer survive because of the derepression of the AIM2 inflammasome. SIRT1 could therefore be a target for the effective treatment of cervical cancer.

Gao HY, Wang W, Luo XG, et al.
Screening of prognostic risk microRNAs for acute myeloid leukemia.
Hematology. 2018; 23(10):747-755 [PubMed] Related Publications
Objectives This study aimed to investigate the risk miRNAs (microRNAs) for AML (acute myeloid leukemia) prognosis and related regulatory mechanisms. Methods MiRNA and gene expression data, as well as clinical data of 176 patients were first downloaded from TCGA. Then miRNAs and genes significantly affecting the survival time based on KM survival curve were identified using Log Rank test. Next, COX proportional-hazard regression analysis was performed to screen the risk miRNAs (P-value < 0.05). Common genes from survival analysis and predicted by miRWalk were used to construct the miRNA regulatory network with the risk miRNAs. Finally, a protein-protein interaction (PPI) network was constructed, as well as functional annotation and pathway enrichment analysis. Results The survival analysis revealed 33 miRNAs and 1,377 genes significantly affecting the survival time. HR values of nine miRNAs (up-regulated hsa-mir-606, 520a, 137, 362, 599, 600, 202, 639and down-regulated 502) were either >1 or <1. The miRNA regulatory network contained 477 nodes and 944 edges. The top ten genes of the constructed PPI network were EGFR, EIF4G1, REL, TOP1, COL14A1, HDAC3, MRPL49, PSMA2, TOP2A and VCAM1 successively. According to pathway enrichment analysis, 6 KEGG pathways and 6 REACTOME pathways were obtained respectively. Conclusion Up-regulated hsa-mir-520a, 599, 606, 137 and 362 may increase the prognostic risk for AML patients via regulating the expression of corresponding target genes, especially COL14A1, HDAC3, REL, EGFR, PSMA2, EIF4G1, MRPL49 and TOP1.

Yasui K, Izumida M, Nakagawa T, et al.
MicroRNA-3662 expression correlates with antiviral drug resistance in adult T-cell leukemia/lymphoma cells.
Biochem Biophys Res Commun. 2018; 501(4):833-837 [PubMed] Related Publications
Interferon regulatory factor (IRF) 4 and the proto-oncogene c-Rel cooperate in growth and antiviral drug resistance of adult T-cell leukemia/lymphoma (ATLL). To elucidate the target of IRF4 and c-Rel in ATLL, we determined the simultaneous binding sites of IRF4 and c-Rel using ChIP-seq technology. Nine genes were identified within 2 kb of binding sites, including MIR3662. Expression of miR-3662 was regulated by IRF4, and to a lesser extent by c-Rel. Cell proliferation was inhibited by knockdown of miR-3662 and expression of miR-3662 was correlated with antiviral drug resistance in ATLL cell lines. Thus, miR-3662 represents a target for therapies against ATLL.

Wang H, Li L, Yin L
Silencing LncRNA LOXL1-AS1 attenuates mesenchymal characteristics of glioblastoma via NF-κB pathway.
Biochem Biophys Res Commun. 2018; 500(2):518-524 [PubMed] Related Publications
The mesenchymal (MES) subtype of glioblastoma (GBM) suggested worse prognosis and a more malignant phenotype in comparison with their proneural (PN) counterpart. The plasticity between PN and MES transcriptome signatures provided clinical intervention with an manner. Few LncRNA, however, have been discovered to take part in the shift between subtypes. Here, we used transcriptomic data and experimental evidences to demonstrate that silencing LncRNA LOXL1-AS1 was a new regulator of NF-κB signaling pathway through repressing RELB directly, resulting in increased marker genes of PN subtype and decreased those of MES.GBM cell proliferation was functionally suppressed by LOXL1-AS1's knockdown expression,. Furthermore, RELB's rescue could reverse LOXL1-AS1's effects partially in GBM malignant behaviors. LOXL1-AS1 could clinically serve as a poor prognostic indicator for GBM patients. In conclusion, our results suggest that LOXL1-AS1 contributes to aggressive biological processes that are related with MES phenotype via NF-κB signaling, which expand our perceptions into the underlying mechanisms in LOXL1-AS1-based and subtype transition adapted medicine for GBM management.

Marazioti A, Lilis I, Vreka M, et al.
Myeloid-derived interleukin-1β drives oncogenic KRAS-NF-κΒ addiction in malignant pleural effusion.
Nat Commun. 2018; 9(1):672 [PubMed] Free Access to Full Article Related Publications
Malignant pleural effusion (MPE) is a frequent metastatic manifestation of human cancers. While we previously identified KRAS mutations as molecular culprits of MPE formation, the underlying mechanism remained unknown. Here, we determine that non-canonical IKKα-RelB pathway activation of KRAS-mutant tumor cells mediates MPE development and this is fueled by host-provided interleukin IL-1β. Indeed, IKKα is required for the MPE-competence of KRAS-mutant tumor cells by activating non-canonical NF-κB signaling. IL-1β fuels addiction of mutant KRAS to IKKα resulting in increased CXCL1 secretion that fosters MPE-associated inflammation. Importantly, IL-1β-mediated NF-κB induction in KRAS-mutant tumor cells, as well as their resulting MPE-competence, can only be blocked by co-inhibition of both KRAS and IKKα, a strategy that overcomes drug resistance to individual treatments. Hence we show that mutant KRAS facilitates IKKα-mediated responsiveness of tumor cells to host IL-1β, thereby establishing a host-to-tumor signaling circuit that culminates in inflammatory MPE development and drug resistance.

Long L, Pang XX, Lei F, et al.
SLC52A3 expression is activated by NF-κB p65/Rel-B and serves as a prognostic biomarker in esophageal cancer.
Cell Mol Life Sci. 2018; 75(14):2643-2661 [PubMed] Free Access to Full Article Related Publications
The human riboflavin transporter-3 (encoded by SLC52A3) plays a prominent role in riboflavin absorption. Interestingly, abnormal expression patterns of SLC52A3 in multiple types of human cancers have been recently noted. However, the molecular mechanisms underlying its dysregulation remain unclear. In this study, we find that SLC52A3 has two transcript variants that differ in the transcriptional start site, and encode different proteins: SLC52A3a and SLC52A3b. Importantly, aberrant expressions of SLC52A3 are associated with stepwise development of esophageal squamous cell carcinoma (ESCC) as well as the survival rates of ESCC patients. Functionally, SLC52A3a, but not SLC52A3b, strongly promotes the proliferation and colony formation of ESCC cells. Furthermore, SLC52A3 5'-flanking regions contain NF-κB p65/Rel-B-binding sites, which are crucial for mediating SLC52A3 transcriptional activity in ESCC cells. Chromatin immunoprecipitation and electrophoretic mobility shift assay reveal that p65/Rel-B bind to 5'-flanking regions of SLC52A3. Accordingly, NF-κB signaling upregulates SLC52A3 transcription upon TNFα stimulation. Taken together, these results elucidate the mechanisms underlying SLC52A3 overexpression in ESCC. More importantly, our findings identify SLC52A3 as both a predictive and prognostic biomarker for this deadly cancer.

Zhang C, Chen B, Jiang K, et al.
Activation of TNF-α/NF-κB axis enhances CRL4B
Mol Oncol. 2018; 12(4):476-494 [PubMed] Free Access to Full Article Related Publications
Cullin 4B, a member of the Cullins, which serve as scaffolds to facilitate the assembly of E3 ligase complexes, is aberrantly expressed in many cancers, including osteosarcoma. Recently, we observed that CUL4B forms the CRL4B

Xiu Y, Dong Q, Li Q, et al.
Stabilization of NF-κB-Inducing Kinase Suppresses MLL-AF9-Induced Acute Myeloid Leukemia.
Cell Rep. 2018; 22(2):350-358 [PubMed] Free Access to Full Article Related Publications
Canonical NF-κB signaling is constitutively activated in acute myeloid leukemia (AML) stem cells and is required for maintenance of the self-renewal of leukemia stem cells (LSCs). However, any potential role for NF-κB non-canonical signaling in AML has been largely overlooked. Here, we report that stabilization of NF-κB-inducing kinase (NIK) suppresses AML. Mechanistically, stabilization of NIK activates NF-κB non-canonical signaling and represses NF-κB canonical signaling. In addition, stabilization of NIK-induced activation of NF-κB non-canonical signaling upregulates Dnmt3a and downregulates Mef2c, which suppresses and promotes AML development, respectively. Importantly, by querying the connectivity MAP using up- and downregulated genes that are present exclusively in NIK-stabilized LSCs, we discovered that verteporfin has anti-AML effects, suggesting that repurposing verteporfin to target myeloid leukemia is worth testing clinically. Our data provide a scientific rationale for developing small molecules to stabilize NIK specifically in myeloid leukemias as an attractive therapeutic option.

Newman AC, Kemp AJ, Drabsch Y, et al.
Autophagy acts through TRAF3 and RELB to regulate gene expression via antagonism of SMAD proteins.
Nat Commun. 2017; 8(1):1537 [PubMed] Free Access to Full Article Related Publications
Macroautophagy can regulate cell signalling and tumorigenesis via elusive molecular mechanisms. We establish a RAS mutant cancer cell model where the autophagy gene ATG5 is dispensable in A549 cells in vitro, yet promotes tumorigenesis in mice. ATG5 represses transcriptional activation by the TGFβ-SMAD gene regulatory pathway. However, autophagy does not terminate cytosolic signal transduction by TGFβ. Instead, we use proteomics to identify selective degradation of the signalling scaffold TRAF3. TRAF3 autophagy is driven by RAS and results in activation of the NF-κB family member RELB. We show that RELB represses TGFβ target promoters independently of DNA binding at NF-κB recognition sequences, instead binding with SMAD family member(s) at SMAD-response elements. Thus, autophagy antagonises TGFβ gene expression. Finally, autophagy-deficient A549 cells regain tumorigenicity upon SMAD4 knockdown. Thus, at least in this setting, a physiologic function for autophagic regulation of gene expression is tumour growth.

House CD, Jordan E, Hernandez L, et al.
NFκB Promotes Ovarian Tumorigenesis via Classical Pathways That Support Proliferative Cancer Cells and Alternative Pathways That Support ALDH
Cancer Res. 2017; 77(24):6927-6940 [PubMed] Free Access to Full Article Related Publications
Understanding the mechanisms supporting tumor-initiating cells (TIC) is vital to combat advanced-stage recurrent cancers. Here, we show that in advanced ovarian cancers NFκB signaling via the RelB transcription factor supports TIC populations by directly regulating the cancer stem-like associated enzyme aldehyde dehydrogenase (ALDH). Loss of RelB significantly inhibited spheroid formation, ALDH expression and activity, chemoresistance, and tumorigenesis in subcutaneous and intrabursal mouse xenograft models of human ovarian cancer. RelB also affected expression of the ALDH gene

Xiao X, Li H, Jin H, et al.
Identification of 11(13)-dehydroivaxillin as a potent therapeutic agent against non-Hodgkin's lymphoma.
Cell Death Dis. 2017; 8(9):e3050 [PubMed] Free Access to Full Article Related Publications
Despite great advancements in the treatment of non-Hodgkin lymphoma (NHL), sensitivity of different subtypes to therapy varies. Targeting the aberrant activation NF-κB signaling pathways in lymphoid malignancies is a promising strategy. Here, we report that 11(13)-dehydroivaxillin (DHI), a natural compound isolated from the Carpesium genus, induces growth inhibition and apoptosis of NHL cells. Multiple signaling cascades are influenced by DHI in NHL cells. PI3K/AKT and ERK are activated or inhibited in a cell type dependent manner, whereas NF-κB signaling pathway was inhibited in all the NHL cells tested. Applying the cellular thermal shift assay, we further demonstrated that DHI directly interacts with IKKα/IKKβ in NHL cells. Interestingly, DHI treatment also reduced the IKKα/IKKβ protein level in NHL cells. Consistent with this finding, knockdown of IKKα/IKKβ inhibits cell proliferation and enhances DHI-induced proliferation inhibition. Overexpression of p65, p52 or RelB partially reverses DHI-induced cell growth inhibition. Furthermore, DHI treatment significantly inhibits the growth of NHL cell xenografts. In conclusion, we demonstrate that DHI exerts anti-NHL effect in vitro and in vivo, through a cumulative effect on NF-κB and other pathways. DHI may serve as a promising lead compound for the therapy of NHL.

Gonzalez-Torres C, Gaytan-Cervantes J, Vazquez-Santillan K, et al.
NF-κB Participates in the Stem Cell Phenotype of Ovarian Cancer Cells.
Arch Med Res. 2017; 48(4):343-351 [PubMed] Related Publications
BACKGROUND: NF-κB is a transcription factor involved in cancer stem cells maintenance of many tumors. Little is known about the specific stem-associated upstream regulators of this pathway in ovarian cancer. The Aim of the study was to analyze the role of the canonical and non-canonical NF-κB pathways in stem cells of ovarian cancer cell lines.
METHODS: Stem cells were isolated using sorting cytometry. Western blot and RT-PCR were used to quantify protein and messenger RNA levels. Loss and gain of function assays were performed using siRNAs and dominant-negative proteins, respectively. NF-κB binding activity was measured with a reporter gene assay. The stem phenotype was estimated with clonogenic assays using soft agar, colony formation, ovospheres formation and in vivo tumorigenicity assays.
RESULTS: The CD44+ subpopulation of SKOV3 ovarian cancer cell line presented higher mRNA levels of key stemness genes, an increased tumorigenic capacity and higher expression of the RelA, RelB and IKKα. When the canonical pathway was inhibited by means of a dominant-negative version of IkBα, the stem cell population was reduced, as shown by a reduced CD44+ subpopulation, a decrease in the expression of the stemness genes and a reduction of the stem phenotype. In addition, IKKα, the main upstream non-canonical kinase, was highly expressed in the CSC population. Accordingly, when IKKα was inhibited using shRNAs, the expression of the stemness genes was reduced.
CONCLUSIONS: This report is the first to show the importance of several elements of both NF-κB pathway in maintaining the ovarian cancer stem cell population.

Slotta C, Schlüter T, Ruiz-Perera LM, et al.
CRISPR/Cas9-mediated knockout of c-REL in HeLa cells results in profound defects of the cell cycle.
PLoS One. 2017; 12(8):e0182373 [PubMed] Free Access to Full Article Related Publications
Cervical cancer is the fourth common cancer in women resulting worldwide in 266,000 deaths per year. Belonging to the carcinomas, new insights into cervical cancer biology may also have great implications for finding new treatment strategies for other kinds of epithelial cancers. Although the transcription factor NF-κB is known as a key player in tumor formation, the relevance of its particular subunits is still underestimated. Here, we applied CRISPR/Cas9n-mediated genome editing to successfully knockout the NF-κB subunit c-REL in HeLa Kyoto cells as a model system for cervical cancers. We successfully generated a homozygous deletion in the c-REL gene, which we validated using sequencing, qPCR, immunocytochemistry, western blot analysis, EMSA and analysis of off-target effects. On the functional level, we observed the deletion of c-REL to result in a significantly decreased cell proliferation in comparison to wildtype (wt) without affecting apoptosis. The impaired proliferative behavior of c-REL-/- cells was accompanied by a strongly decreased amount of the H2B protein as well as a significant delay in the prometaphase of mitosis compared to c-REL+/+ HeLa Kyoto cells. c-REL-/- cells further showed significantly decreased expression levels of c-REL target genes in comparison to wt. In accordance to our proliferation data, we observed the c-REL knockout to result in a significantly increased resistance against the chemotherapeutic agents 5-Fluoro-2'-deoxyuridine (5-FUDR) and cisplatin. In summary, our findings emphasize the importance of c-REL signaling in a cellular model of cervical cancer with direct clinical implications for the development of new treatment strategies.

Velmurugan KR, Varghese RT, Fonville NC, Garner HR
High-depth, high-accuracy microsatellite genotyping enables precision lung cancer risk classification.
Oncogene. 2017; 36(46):6383-6390 [PubMed] Free Access to Full Article Related Publications
There remains a large discrepancy between the known genetic contributions to cancer and that which can be explained by genomic variants, both inherited and somatic. Recently, understudied repetitive DNA regions called microsatellites have been identified as genetic risk markers for a number of diseases including various cancers (breast, ovarian and brain). In this study, we demonstrate an integrated process for identifying and further evaluating microsatellite-based risk markers for lung cancer using data from the cancer genome atlas and the 1000 genomes project. Comparing whole-exome germline sequencing data from 488 TCGA lung cancer samples to germline exome data from 390 control samples from the 1000 genomes project, we identified 119 potentially informative microsatellite loci. These loci were found to be able to distinguish between cancer and control samples with sensitivity and specificity ratios over 0.8. Then these loci, supplemented with additional loci from other cancers and controls, were evaluated using a target enrichment kit and sample-multiplexed nextgen sequencing. Thirteen of the 119 risk markers were found to be informative in a well powered study (>0.99 for a 0.95 confidence interval) using high-depth (579x±315) nextgen sequencing of 30 lung cancer and 89 control samples, resulting in sensitivity and specificity ratios of 0.90 and 0.94, respectively. When 8 loci harvested from the bioinformatic analysis of other cancers are added to the classifier, then the sensitivity and specificity rise to 0.93 and 0.97, respectively. Analysis of the genes harboring these loci revealed two genes (ARID1B and REL) and two significantly enriched pathways (chromatin organization and cellular stress response) suggesting that the process of lung carcinogenesis is linked to chromatin remodeling, inflammation, and tumor microenvironment restructuring. We illustrate that high-depth sequencing enables a high-precision microsatellite-based risk classifier analysis approach. This microsatellite-based platform confirms the potential to create clinically actionable diagnostics for lung cancer.

Barth TFE, Kraus JM, Lausser L, et al.
Comparative gene-expression profiling of the large cell variant of gastrointestinal marginal-zone B-cell lymphoma.
Sci Rep. 2017; 7(1):5963 [PubMed] Free Access to Full Article Related Publications
Gastrointestinal (g.i.) large cell lymphoma is currently regarded as diffuse large B-cell lymphoma (DLBCL) despite a more favorable clinical outcome compared to other DLBCL. Cluster analyses on a transcriptome signature of NF-κB target genes of 30 g.i. marginal zone B-cell lymphomas (MZBL; 8 g.i. MZBL, 22 large cell MZBL - among them 9 with coexisting small cell component) and 6 DLBCL (3 activated B-cell like (ABC), 3 germinal center-like (GCB)) reveals a distinct pattern. The distinctiveness of large cell MZBL samples is further confirmed by a cohort of 270 available B-cell lymphoma and B-cell in silico profiles. Of the NF-κB genes analyzed, c-REL was overexpressed in g.i. MZBL. c-REL amplification was limited to 6/22 large cell MZBL including the large cell component of 2/9 composite small cell/large cell lymphomas, and c-Rel protein expression was found in the large cell compartment of composite lymphomas. Classification experiments on DLBCL and large cell MZBL profiles support the concept that the large cell MZBL is a distinct type of B-cell lymphoma.

Nandakumar A, Uwatoko F, Yamamoto M, et al.
Radiation-induced Epstein-Barr virus reactivation in gastric cancer cells with latent EBV infection.
Tumour Biol. 2017; 39(7):1010428317717718 [PubMed] Related Publications
Epstein-Barr virus, a ubiquitous human herpes virus with oncogenic activity, can be found in 6%-16% of gastric carcinomas worldwide. In Epstein-Barr virus-associated gastric carcinoma, only a few latent genes of the virus are expressed. Ionizing irradiation was shown to induce lytic Epstein-Barr virus infection in lymphoblastoid cell lines with latent Epstein-Barr virus infection. In this study, we examined the effect of ionizing radiation on the Epstein-Barr virus reactivation in a gastric epithelial cancer cell line (SNU-719, an Epstein-Barr virus-associated gastric carcinoma cell line). Irradiation with X-ray (dose = 5 and 10 Gy; dose rate = 0.5398 Gy/min) killed approximately 25% and 50% of cultured SNU-719 cells, respectively, in 48 h. Ionizing radiation increased the messenger RNA expression of immediate early Epstein-Barr virus lytic genes (BZLF1 and BRLF1), determined by real-time reverse transcription polymerase chain reaction, in a dose-dependent manner at 48 h and, to a slightly lesser extent, at 72 h after irradiation. Similar findings were observed for other Epstein-Barr virus lytic genes (BMRF1, BLLF1, and BcLF1). After radiation, the expression of transforming growth factor beta 1 messenger RNA increased and reached a peak in 12-24 h, and the high-level expression of the Epstein-Barr virus immediate early genes can convert latent Epstein-Barr virus infection into the lytic form and result in the release of infectious Epstein-Barr virus. To conclude, Ionizing radiation activates lytic Epstein-Barr virus gene expression in the SNU-719 cell line mainly through nuclear factor kappaB activation. We made a brief review of literature to explore underlying mechanism involved in transforming growth factor beta-induced Epstein-Barr virus reactivation. A possible involvement of nuclear factor kappaB was hypothesized.

Shen M, Zhou L, Zhou P, et al.
Lymphotoxin β receptor activation promotes mRNA expression of RelA and pro-inflammatory cytokines TNFα and IL-1β in bladder cancer cells.
Mol Med Rep. 2017; 16(1):937-942 [PubMed] Related Publications
The role of inflammation in tumorigenesis and development is currently well established. Lymphotoxin β receptor (LTβR) activation induces canonical and noncanonical nuclear factor (NF)‑κB signaling pathways, which are linked to inflammation‑induced carcinogenesis. In the present study, 5,637 bladder cancer cells were cultured and the activation of LTβR was induced by functional ligand, lymphotoxin (LT) α1β2, and silencing with shRNA. Reverse transcription‑quantitative polymerase chain reaction was utilized to detect the mRNA expression levels of NF‑κB family members RelA and RelB, cytokines including LTα, LTβ, tumor necrosis factor (TNF)α, TNF superfamily member 14, interleukin (IL)‑6 and IL‑1β, and proliferation‑related genes including CyclinD1 and Survivin. The expression of phospho‑p65 was determined by western blotting. Activation of LTβR on bladder cancer 5,637 cells was demonstrated to upregulate the mRNA expression levels of the RELA proto‑oncogene, RelA, by 2.5‑fold compared with unstimulated cells, while no significant change was observed in the RELB proto‑oncogene NF‑κB member mRNA levels. Expression of pro‑inflammatory cytokines tumor necrosis factor (TNF)α and interleukin (IL)‑1β mRNA levels were significantly increased nearly 5‑fold and 1.5‑fold, respectively, following LTβR activation compared with unstimulated cells. The LTβR‑induced upregulation of RelA, TNFα and IL‑1β was decreased by ~33, 27, and 26% respectively when LTβR was silenced via short hairpin RNA. Activation of LTβR had no effect on 5,637 cell growth, despite CyclinD1 and Survivin mRNA levels increasing by ~2.7 and 1.3‑fold, respectively, compared with unstimulated cells. In conclusion, activation of LTβR induced the expression of RelA mRNA levels. LTβR activation might be an important mediator in promoting an inflammatory microenvironment in bladder cancer, via the upregulation of TNFα and IL‑1β mRNA levels. LTβR may be a potential therapeutic target for bladder cancer.

Zhao Y, Min L, Xu C, et al.
Construction of disease-specific transcriptional regulatory networks identifies co-activation of four gene in esophageal squamous cell carcinoma.
Oncol Rep. 2017; 38(1):411-417 [PubMed] Related Publications
Even though various molecules may serve as biomarkers, little is known concerning the mechanisms underlying the carcinogenesis of ESCC, particularly the transcriptional regulatory network. Thus, in the present study, paired ESCC and non-cancerous (NC) tissues were assayed by Affymetrix microarray assays. Passing Attributes between Networks for Data Assimilation (PANDA) was used to construct networks between transcription factors (TFs) and their targets. AnaPANDA program was applied to compare the regulatory networks. A hypergeometric distribution model-based target profile similarity analysis was utilized to find co-activation effects using both TF-target networks and differential expression data. There were 1,116 genes upregulated and 1,301 genes downregulated in ESCC compared with NC tissues. In TF-target networks, 16,970 ESCC-specific edges and 9,307 NC-specific edges were identified. Edge enrichment analysis by AnaPANDA indicated 17 transcription factors (NFE2L2, ELK4, PAX6, TLX1, ESR1, ZNF143, TP53, REL, ELF5, STAT1, TBP, NHLH1, FOXL1, SOX9, STAT3, ELK1, and HOXA5) suppressed in ESCC and 5 (SPIB, BRCA1, MZF1, MAFG and NFE2L1) activated in ESCC. For SPIB, MZF1, MAFG and NFE2L1, a strong and significant co-activation effect among them was detected in ESCC. In conclusion, the construction of transcriptional regulatory networks found SPIB, MZF1, MAFG and NFE2L1 co-activated in ESCC, which provides distinctive insight into the carcinogenesis mechanism of ESCC.

Griesinger AM, Witt DA, Grob ST, et al.
NF-κB upregulation through epigenetic silencing of LDOC1 drives tumor biology and specific immunophenotype in Group A ependymoma.
Neuro Oncol. 2017; 19(10):1350-1360 [PubMed] Free Access to Full Article Related Publications
Background: Inflammation has been identified as a hallmark of high-risk Group A (GpA) ependymoma (EPN). Chronic interleukin (IL)-6 secretion from GpA tumors drives an immune suppressive phenotype by polarizing infiltrating monocytes. This study determines the mechanism by which IL-6 is dysregulated in GpA EPN.
Methods: Twenty pediatric GpA and 21 pediatric Group B (GpB) EPN had gene set enrichment analysis for MSigDB Hallmark gene sets performed. Protein and RNA from patients and cell lines were used to validate transcriptomic findings. GpA cell lines 811 and 928 were used for in vitro experiments performed in this study.
Results: The nuclear factor-kappaB (NF-κB) pathway is a master regulator of IL-6 and a signaling pathway enriched in GpA compared with GpB EPN. Knockdown of NF-κB led to significant downregulation of IL-6 in 811 and 928. NF-κB activation was independent of tumor necrosis factor alpha (TNF-α) stimulation in both cell lines, suggesting that NF-κB hyperactivation is mediated through an alternative mechanism. Leucine zipper downregulated in cancer 1 (LDOC1) is a known transcriptional repressor of NF-κB. In many cancers, LDOC1 promoter is methylated, which inhibits gene transcription. We found decreased LDOC1 gene expression in GpA compared with GpB EPN, and in other pediatric brain tumors. EPN cells treated with 5AZA-DC, demethylated LDOC1 regulatory regions, upregulated LDOC1 expression, and concomitantly decreased IL-6 secretion. Stable knockdown of LDOC1 in EPN cell lines resulted in a significant increase in gene transcription of v-rel avian reticuloendotheliosis viral oncogene homolog A, which correlated to an increase in NF-κB target genes.
Conclusion: These results suggest that epigenetic silencing of LDOC1 in GpA EPN regulates tumor biology and drives inflammatory immune phenotype.

Domińska K, Kowalska K, Matysiak ZE, et al.
Regulation of mRNA gene expression of members of the NF-κB transcription factor gene family by angiotensin II and relaxin 2 in normal and cancer prostate cell lines.
Mol Med Rep. 2017; 15(6):4352-4359 [PubMed] Related Publications
An increasing number of researchers are focusing on the influence of local peptide hormones such as angiotensin II (Ang II) and relaxin 2 (RLN2) in the regulation of inflammation and carcinogenesis. The interaction between the renin‑angiotensin system (RAS) and relaxin family peptide system (RFPS) is known to influence the proliferation, adhesion and migration of normal and cancer prostate cell lines. The aim of the present study was to evaluate changes in the expression of nuclear factor‑κB subunit 1 (NFKB1), nuclear factor‑κB subunit 2 (NFKB2), REL proto‑oncogene nuclear factor‑κB p65 subunit (REL), RELA proto‑oncogene nuclear factor‑κB subunit (RELA) and RELB proto‑oncogene nuclear factor‑κB subunit (RELB) mRNA caused by Ang II and RLN2. The members of NF‑kB family are involved in many processes associated with cancer development and metastasis. Reverse transcription‑quantitative polymerase chain reaction analysis identified that both peptide hormones have an influence on the relative expression of nuclear factor‑κB. Following treatment with either peptide, NFKB1 expression was downregulated in all prostate cancer cell lines (LNCaP, DU‑145 and PC3), but not in normal epithelial cells (PNT1A). Conversely, RELB mRNA was enhanced only in non‑cancerous prostate cells. RELA expression was strongly stimulated in the most aggressive cell line, whereas REL mRNA was unchanged. In many cases, the effect was strictly dependent on the cell line and/or the type of peptide: Ang II increased expression of both RELA and REL genes in the androgen‑dependent cell line while RLN2 enhanced NFKB2 and RELA mRNA in androgen‑independent cells (DU‑145). Further research is needed to understand the regulation of NF‑κB family members by key renin‑angiotensin system and RFPS peptides in prostate cancer cells; however, prostate carcinogenesis appears to be influenced by the balance between the cross‑regulation of nuclear factor‑κB (NF‑κB) and androgen receptor pathways by Ang II and relaxin 2.

Huang YX, Chen XT, Guo KY, et al.
Sunitinib Induces NK-κB-dependent NKG2D Ligand Expression in Nasopharyngeal Carcinoma and Hepatoma Cells.
J Immunother. 2017; 40(5):164-174 [PubMed] Related Publications
Multitargeted tyrosine kinase inhibitors (MTKIs) have been shown to combine with natural killer (NK) cell adoptive transfer for the treatment in various cancers. MTKIs sensitize cancer cells to NK cell therapy through upregulation of nature killer group 2 member D ligands (NKG2DLs) on tumor cells. However, the molecular mechanism of MTKIs-mediated upregulation of NKG2DLs is still unknown. In this study, we confirmed sunitinib induced downregulation of its targets, such as vascular endothelial growth factor, platelet-derived growth factor, and c-kit in multiple-drug-resistant nasopharyngeal carcinoma cell line CNE2/DDP and hepatoma cell line HepG2. Then, we further showed sunitinib induced cell proliferation inhibition, apoptosis, and DNA damage in CNE2/DDP and HepG2 cells. Coculture experiments showed that sunitinib-treated CNE2/DDP and HepG2 cells were able to increase the activation and cytotoxicity of NK cells. Quantitative polymerase chain reaction results showed that sunitinib upregulated NKG2DLs, apoptotic genes, DNA damage repair genes, and nuclear factor (NF)-κβ family genes. Silencing of NF-κβ1, NF-κβ2, or RelB (NF-κβ pathway) inhibited sunitinib-induced upregulation of NKG2DLs. Taken together, we concluded that sunitinib upregulated NKG2DLs through NF-κβ signaling noncanonical pathway which might mediate higher cytotoxic sensitivity of CNE2/DDP and HepG2 cells to NK cells.

Rohban MH, Singh S, Wu X, et al.
Systematic morphological profiling of human gene and allele function via Cell Painting.
Elife. 2017; 6 [PubMed] Free Access to Full Article 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.

Nguyen CH, Brenner S, Huttary N, et al.
AHR/CYP1A1 interplay triggers lymphatic barrier breaching in breast cancer spheroids by inducing 12(S)-HETE synthesis.
Hum Mol Genet. 2016; 25(22):5006-5016 [PubMed] Related Publications
A causal link between overexpression of aryl hydrocarbon receptor (AHR) and its target cytochrome P450 1A1 (CYP1A1) and metastatic outgrowth of various cancer entities has been established. Nevertheless, the mechanism how AHR/CYP1A1 support metastasis formation is still little understood. In vitro we discovered a potential mechanism facilitating tumour dissemination based on the production of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE). Utilising a three-dimensional lymph endothelial cell (LEC) monolayer & MDA-MB231 breast cancer cell spheroid co-culture model in combination with knock-down approach allowed elucidation of the molecular/biochemical basis of AHR/CYP1A1-induced tumour breaching through the LEC barrier. Enzyme immunoassay evidenced the potential of recombinant CYP1A1 to synthesise 12(S)-HETE in vitro and qPCR and Western blotting measured gene and protein expression in specific experimental settings. In detail, AHR induced CYP1A1 expression and 12(S)-HETE secretion in tumour spheroids, which caused LEC junction retraction thereby forming large discontinuities allowing transmigration of the tumour. This was enforced by the activating AHR ligand 6-formylindolo (3,3-b)carbazole (FICZ), or inhibited by the AHR antagonist 3,3’-diindolylmethane (DIM) as well as by siRNA against AHR and CYP1A1. AHR and NF-κB were negatively cross talking and therefore, the inhibition of AHR (but not CYP1A1) induced RELA, RELB, NFKB1, NFKB2 and the NF-κB target MMP1, which itself promotes tumour intravasation by a mechanism that is different from 12(S)-HETE. Conversely, the inhibition of NFKB2 induced AHR, CYP1A1 and 12(S)-HETE synthesis. The approved clinical drugs guanfacine and vinpocetine, which inhibit CYP1A1 and NF-κB, respectively, significantly inhibited LEC barrier breaching in vitro indicating an option to reduce metastatic dissemination.

Hu X, Baytak E, Li J, et al.
The relationship of REL proto-oncogene to pathobiology and chemoresistance in follicular and transformed follicular lymphoma.
Leuk Res. 2017; 54:30-38 [PubMed] Related Publications
Follicular lymphoma (FL) is a common type of indolent lymphoma that occasionally transforms to more aggressive B-cell lymphomas. These transformed follicular lymphomas (tFL) are often associated with chemoresistance whose mechanisms are currently unknown. REL, a proto-oncogene located on frequently amplified 2p16.1-p15 locus, promotes tumorigenesis in many cancer types through deregulation of the NF-κB pathway; however, its role in FL pathobiology or chemoresistance has not been addressed. Here, we evaluated REL gene copy number by q-PCR on FFPE FL tumor samples, and observed REL amplification in 30.4% of FL cases that was associated with weak elevation of transcript levels. PCR-Sanger analysis did not show any somatic mutation in FL tumors. In support of a marginal oncogenic role, a REL-transduced FL cell line was positively selected under limiting serum conditions. Interestingly, reanalysis of previously reported gene expression profiles revealed significant enrichment of DNA damage-induced repair and cell cycle arrest pathways in tFL tumors with high REL expression compared to those with low REL expression consistent with the critical role of c-REL in genotoxicity-induced NF-κB signaling, which was reported to lead to drug resistance. In addition to DNA damage repair genes such as ATM and BRCA1, anti-apoptotic BCL2 was significantly elevated in REL-high FL and tFL tumors. Altogether these data suggest that other genes located in amplified 2p16.1-p15 locus may have more oncogenic role in FL etiology; however, high REL expression may be useful as a predictive biomarker of response to immunochemotherapy, and inhibition of c-REL may potentially sensitize resistant FL or tFL cells to chemotherapy.

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