Gene Summary

Gene:TNFAIP3; TNF alpha induced protein 3
Aliases: A20, AISBL, OTUD7C, TNFA1P2
Summary:This gene was identified as a gene whose expression is rapidly induced by the tumor necrosis factor (TNF). The protein encoded by this gene is a zinc finger protein and ubiqitin-editing enzyme, and has been shown to inhibit NF-kappa B activation as well as TNF-mediated apoptosis. The encoded protein, which has both ubiquitin ligase and deubiquitinase activities, is involved in the cytokine-mediated immune and inflammatory responses. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:tumor necrosis factor alpha-induced protein 3
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (61)
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.

  • MYD88
  • Apoptosis
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • beta Catenin
  • Immunohistochemistry
  • Gene Expression Profiling
  • Single Nucleotide Polymorphism
  • DNA Mutational Analysis
  • Neoplasm Proteins
  • Cancer RNA
  • Chromosome 6
  • Gene Deletion
  • Drug Resistance
  • Nuclear Proteins
  • FISH
  • Cancer Gene Expression Regulation
  • Oligonucleotide Array Sequence Analysis
  • NF-kappa B
  • Biomarkers, Tumor
  • Mutation
  • MicroRNAs
  • Notch Receptors
  • Signal Transduction
  • Splenic Neoplasms
  • Up-Regulation
  • Cell Proliferation
  • Western Blotting
  • MALT Lymphoma
  • B-Cell Lymphoma
  • High-Throughput Nucleotide Sequencing
  • Diffuse Large B-Cell Lymphoma
  • Hodgkin Lymphoma
  • siRNA
  • Transcription
  • Messenger RNA
  • HEK293 Cells
  • Tumor Virus Infections
  • Breast Cancer
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: TNFAIP3 (cancer-related)

Nezos A, Gkioka E, Koutsilieris M, et al.
TNFAIP3 F127C Coding Variation in Greek Primary Sjogren's Syndrome Patients.
J Immunol Res. 2018; 2018:6923213 [PubMed] Free Access to Full Article Related Publications
Tumor necrosis factor, alpha-induced protein 3 (

Wang Y, Wang L, Sui M
Long non-coding RNA H19 promotes proliferation of Hodgkin's lymphoma via AKT pathway.
J BUON. 2018 Nov-Dec; 23(6):1825-1831 [PubMed] Related Publications
PURPOSE: To explore whether lncRNA (Long non-coding RNA) H19 could promote the development of Hodgkin's lymphoma (HL) by regulating cell proliferation via AKT pathway.
METHODS: H19 expressions in 60 HL tissues, 40 RH (reactive hyperplasia of lymph nodes) tissues, L428, A20 and Ly1 cell lines were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). H19 siRNA and pcDNA-H19 were constructed. Cell viability after altering H19 expression was detected by EdU and cell counting kit-8 (CCK-8) assay. The mRNA level of AKT in HL tissues and RH tissues was detected by qRT-PCR. The relationship between AKT and H19 was further detected by Western blot.
RESULTS: H19 was overexpressed in HL tissues and cell lines compared with those of controls. HL patients with huge lump and in Ann Arbor stage III-IV presented higher expression of H19. Besides, H19 expression was negatively correlated to overall survival (OS) of HL patients. In vitro experiments suggested that H19 downregulation decreased proliferation and viability of HL cells. AKT expression was upregulated in HL tissues compared with RH tissues, and was positively regulated by H19. Western blot results also indicated that H19 overexpression upregulated protein expression of AKT in HL cells.
CONCLUSIONS: Overexpressed lncRNA H19 promotes HL development by stimulating proliferation of HL cells via AKT pathway.

Sun F, Ni Y, Zhu H, et al.
microRNA-29a-3p, Up-Regulated in Human Gastric Cells and Tissues with H.Pylori Infection, Promotes the Migration of GES-1 Cells via A20-Mediated EMT Pathway.
Cell Physiol Biochem. 2018; 51(3):1250-1263 [PubMed] Related Publications
BACKGROUND/AIMS: Helicobacter pylori (H. pylori) infection is closely related to human gastric mucosa-associated diseases. Several recent studies on miRNAs have expanded our insights on H.pylori pathogenesis. This study aimed to investigate the biological roles and underlying molecular mechanisms of miR-29a-3p in human gastric cells and tissues with H.pylori infection.
METHODS: miR-29a-3p expression was quantified by quantitative RT-PCR (qRT-PCR). A miR-29a-3p target gene was validated by bioinformatics analysis, western blotting and dual luciferase reporter gene assays. Western blotting and immunohistochemistry (IHC) assay were performed to detect the protein expression. Transwell assay was used to determine the cell migration ability.
RESULTS: MiR-29a-3p was up-regulated in H.pylori-positive gastric mucosa tissues and H.pylori-infected gastric cells. The up-regulation of miR-29a-3p was dose-dependent in BGC-823 and GES-1 cells infected with H.pylori. Using gain- and loss-of-function experiments in vitro, we demonstrated that miR-29a-3p promoted the migration of gastric epithelial cells. We further characterized A20 as a direct target of miR-29a-3p. The expression of A20 was decreased in H.pylori-positive gastric mucosa tissues compared with H.pylori-negative gastric mucosa tissues. A20 downregulation was time- and dose-dependent in GES-1 and BGC-823 cells infected with H.pylori. In GES-1 and BGC-823 cells infected with H.pylori, the miR-29a-3p mimic significantly blocked A20 expression, which suggests that H.pylori decreased A20 expression through up-regulating miR-29a-3p in GES-1 and BGC-823 cells infected with H.pylori. The knockdown of A20 by siRNA enhanced the migration of human gastric epithelial cells and promoted the expression of Snail, Vimentin, and N-cadherin and inhibited the expression of E-cadherin.
CONCLUSION: The miR-29a-3p may act as a tumor promotive miRNA by regulating cells migration through directly targeting of A20 gene in human gastric epithelial cells infected with H.pylori.

Wenzl K, Manske MK, Sarangi V, et al.
Loss of TNFAIP3 enhances MYD88
Blood Cancer J. 2018; 8(10):97 [PubMed] Free Access to Full Article Related Publications
MYD88 mutations are one of the most recurrent mutations in hematologic malignancies. However, recent mouse models suggest that MYD88

Lee E, Ouzounova M, Piranlioglu R, et al.
The pleiotropic effects of TNFα in breast cancer subtypes is regulated by TNFAIP3/A20.
Oncogene. 2019; 38(4):469-482 [PubMed] Free Access to Full Article Related Publications
TNFα is a pleiotropic cytokine which fuels tumor cell growth, invasion, and metastasis in some malignancies, while in others it induces cytotoxic cell death. However, the molecular mechanism by which TNFα exerts its diverse effects on breast cancer subtypes remains elusive. Using in vitro assays and mouse xenografts, we show here that TNFα contributes to the aggressive properties of triple negative breast cancer (TNBC) cell lines via upregulation of TNFAIP3(A20). In a striking contrast, TNFα induces a potent cytotoxic cell death in luminal (ER+) breast cancer cell lines which fail to upregulate A20 expression. Overexpression of A20 not only protects luminal breast cancer cell lines from TNFα-induced cell death via inducing HSP70-mediated anti-apoptotic pathway but also promotes a robust EMT/CSC phenotype by activating the pStat3-mediated inflammatory signaling. Furthermore, A20 overexpression in luminal breast cancer cells induces aggressive metastatic properties in mouse xenografts via generating a permissive inflammatory microenvironment constituted by granulocytic-MDSCs. Collectively, our results reveal a mechanism by which A20 mediates pleiotropic effects of TNFα playing role in aggressive behaviors of TNBC subtype while its deficiency results in TNFα-induced apoptotic cell death in luminal breast cancer subtype.

Song P, Zhang J, Shang C, Zhang L
Alectinib treatment response in lung adenocarcinoma patient with novel EML4-ALK variant.
Thorac Cancer. 2018; 9(10):1327-1332 [PubMed] Free Access to Full Article Related Publications
Common gene fusion of the ALK gene is fusion of the ALK tyrosine kinase area and the 5'end of EML4. Seventeen EML4-ALK fusion variants have been reported. Herein, we report a novel EML4-ALK variant detected by next-generation sequencing in a 36-year-old female lung adenocarcinoma patient who experienced disease progression after six months of alectinib treatment. Second generation sequencing revealed an EML4-ALK fusion variant in which intron 19 of EML4 was fused to exon 20 of ALK. This is the first case of EML4-ALK (E19: A20) fusion to be reported. Alectinib may show unsatisfactory therapeutic effects for this kind of ALK fusion.

Yang M, Yu X, Li X, et al.
TNFAIP3 is required for FGFR1 activation-promoted proliferation and tumorigenesis of premalignant DCIS.COM human mammary epithelial cells.
Breast Cancer Res. 2018; 20(1):97 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Although ductal carcinoma in situ (DCIS) is a non-invasive breast cancer, many DCIS lesions may progress to invasive cancer and the genes and pathways responsible for its progression are largely unknown. FGFR1 plays an important role in cell proliferation, differentiation and carcinogenesis. The purpose of this study is to examine the roles of FGFR1 signaling in gene expression, cell proliferation, tumor growth and progression in a non-invasive DCIS model.
METHODS: DCIS.COM cells were transfected with an empty vector to generate DCIS-Ctrl cells. DCIS-iFGFR1 cells were transfected with an AP20187-inducible iFGFR1 vector to generate DCIS-iFGFR1 cells. iFGFR1 consists of the v-Src myristoylation membrane-targeting sequence, FGFR1 cytoplasmic domain and the AP20187-inducible FKBP12 dimerization domain, which simulates FGFR1 signaling. The CRISPR/Cas9 system was employed to knockout ERK1, ERK2 or TNFAIP3 in DCIS-iFGFR1 cells. Established cell lines were treated with/without AP20187 and with/without FGFR1, MEK, or ERK1/2 inhibitor. The effects of these treatments were determined by Western blot, RNA-Seq, real-time RT-PCR, cell proliferation, mammosphere growth, xenograft tumor growth, and tumor histopathological assays.
RESULTS: Activation of iFGFR1 signaling in DCIS-iFGFR1 cells enhanced ERK1/2 activities, induced partial epithelial-to-mesenchymal transition (EMT) and increased cell proliferation. Activation of iFGFR1 signaling promoted DCIS growth and progression to invasive cancer derived from DCIS-iFGFR1 cells in mice. Activation of iFGFR1 signaling also altered expression levels of 946 genes involved in cell proliferation, migration, cancer pathways, and other molecular and cellular functions. TNFAIP3, a ubiquitin-editing enzyme, is upregulated by iFGFR1 signaling in a FGFR1 kinase activity and in an ERK2-dependent manner. Importantly, TNFAIP3 knockout not only inhibited the AP20187-induced proliferation and tumor growth of DCIS-iFGFR1 cells, but also further reduced baseline proliferation and tumor growth of DCIS-iFGFR1 cells without AP20187 treatment.
CONCLUSIONS: Activation of iFGFR1 promotes ERK1/2 activity, EMT, cell proliferation, tumor growth, DCIS progression to invasive cancer, and altered the gene expression profile of DCIS-iFGFR1 cells. Activation of iFGFR1 upregulated TNFAIP3 in an ERK2-dependent manner and TNFAIP3 is required for iFGFR1 activation-promoted DCIS.COM cell proliferation, mammosphere growth, tumor growth and progression. These results suggest that TNFAIP3 may be a potential target for inhibiting DCIS growth and progression promoted by FGFR1 signaling.

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.

Mazzio EA, Lewis CA, Elhag R, Soliman KF
Effects of Sepantronium Bromide (YM-155) on the Whole Transcriptome of MDA-MB-231 Cells: Highlight on Impaired ATR/ATM Fanconi Anemia DNA Damage Response.
Cancer Genomics Proteomics. 2018 Jul-Aug; 15(4):249-264 [PubMed] Free Access to Full Article Related Publications
Sepantronium bromide (YM-155) is believed to elicit apoptosis and mitotic arrest in tumor cells by reducing (BIRC5, survivin) mRNA. In this study, we monitored changes in survivin mRNA and protein after treating MDA-MB-231 cells with YM-155 concurrent with evaluation of whole transcriptomic (WT) mRNA and long intergenic non-coding RNA at 2 time points: 8 h sub-lethal (83 ng/mL) and 20 h at the LC

Wang D, Jiang W, Zhu F, et al.
Modulation of the tumor microenvironment by intratumoral administration of IMO-2125, a novel TLR9 agonist, for cancer immunotherapy.
Int J Oncol. 2018; 53(3):1193-1203 [PubMed] Related Publications
The objective of cancer immunotherapy is to prime the host's immune system to recognize and attack malignant tumor cells. IMO‑2125, a Toll‑like receptor 9 (TLR9) agonist, exhibited potent antitumor effects in the murine syngeneic A20 lymphoma and the CT26 colon carcinoma models. IMO‑2125 exhibited superior A20 antitumor activity when injected intratumorally (i.t.) compared with equivalent subcutaneous doses. In mice bearing dual CT26 grafts, the i.t. injection of right flank tumors elicited infiltration of cluster of differentiation (CD)3+ T lymphocytes into tumors, resulting in the regression of injected and uninjected left flank tumors. Depletion of CD8+, but not CD4+, T‑cells abrogated the IMO‑2125‑mediated antitumor response, suggesting that CD8+ lymphocytes are required for the antitumor activity. In mice harboring right flank CT26 and left flank β‑galactosidase (β‑gal)‑expressing CT26.CL25 grafts, the i.t. administration of IMO‑2125 to the CT26 graft resulted in potent and dose‑dependent antitumor activity against the two grafts. Splenic T‑cells isolated from these mice responded to AH1 antigen (present in the two tumors) and β‑gal antigen (present only in CT26.CL25) in an interferon γ enzyme‑linked immunospot assay, suggesting the clonal expansion of T‑cells directed against antigens from the two tumors. Mice with ablated CT26 tumors by previous IMO‑2125 treatment rejected re‑implanted CT26 tumor cells, but not A20 tumor cells, demonstrating that the initial IMO‑2125 treatment created a long‑lived tumor‑specific immune memory of CT26 antigens. A quantitative increase in CD3+ T lymphocytes in injected A20 tumors and an upregulation of selected checkpoint genes, including indoleamine 2,3‑dioxygenase (IDO)‑1, IDO‑2, programmed cell death protein-1 (PD-1); programmed cell death protein ligand 1 (PD-L1), carcinoembryonic antigen‑related cell adhesion molecule 1, tumor necrosis factor receptor superfamily member 4 (OX40), OX40 ligand, T‑cell immunoglobulin and mucin‑domain‑containing 3 protein, lymphocyte‑activation gene 3, cytotoxic T‑lymphocyte‑associated protein 4, were observed following IMO‑2125 treatment. IMO‑2125 also increased immune checkpoint gene expression in injected and uninjected contralateral CT26 tumors, suggesting that the co‑administration of anti‑CTLA‑4, anti‑PD‑1 or anti‑PD‑L1 therapies with IMO‑2125 may provide additional therapeutic efficacy.

Hiemcke-Jiwa LS, Leguit RJ, Snijders TJ, et al.
Molecular analysis in liquid biopsies for diagnostics of primary central nervous system lymphoma: Review of literature and future opportunities.
Crit Rev Oncol Hematol. 2018; 127:56-65 [PubMed] Related Publications
Primary central nervous system lymphoma (PCNSL) is an aggressive lymphoma with a poor prognosis, for which accurate and timely diagnosis is of utmost importance. Unfortunately, diagnosis of PCNSL can be challenging and a brain biopsy (gold standard for diagnosis) is an invasive procedure with the risk of major complications. Thus, there is an urgent need for an alternative strategy to diagnose and monitor these lymphomas. Currently, liquid biopsies from cerebrospinal fluid (CSF) are used for cytomorphologic and flow cytometric analysis. Recently, new biomarkers such as genetic mutations and interleukins have been identified in these liquid biopsies, further expanding the diagnostic armamentarium. In this review we present an overview of genetic aberrations (>70) reported in this unique lymphoma. Of these genes, we have selected those that are reported in ≥3 studies. Half of the selected genes are implicated in the NFκB pathway (CARD11, CD79B, MYD88, TBL1XR1 and TNFAIP3), while the other half are not related to this pathway (CDKN2A, ETV6, PIM1, PRDM1 and TOX). Although this underlines the crucial role of the NFκB pathway in PCNSL, CD79B and MYD88 are at present the only genes mentioned in liquid biopsy analysis. Finally, a stepwise approach is proposed for minimally invasive liquid biopsy analysis and work-up of PCNSL, incorporating molecular analysis. Prioritization and refinements of this approach can be constructed based upon multidisciplinary collaboration as well as novel scientific insights.

Liu K, Yao H, Wen Y, et al.
Functional role of a long non-coding RNA LIFR-AS1/miR-29a/TNFAIP3 axis in colorectal cancer resistance to pohotodynamic therapy.
Biochim Biophys Acta Mol Basis Dis. 2018; 1864(9 Pt B):2871-2880 [PubMed] Related Publications
Colorectal Cancer (CRC) is one of the most common digestive system malignant tumors. Recently, PDT has been used as a first-line treatment for colon cancer; however, limited curative effect was obtained due to resistance of CRC to PDT. During the past decades, accumulating CRC-related long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and mRNAs have been reported to exert diverse functions through various biological processes; their dysregulation might trigger and/or promote the pathological changes. Herein, we performed microarrays analysis to identify dysregulated lncRNAs, miRNAs and mRNAs in PDT-treated HCT116 cells to figure out the lncRNA-miRNA interactions related to the resistance of CRC to PDT treatment, and the downstream mRNA target, as well as the molecular mechanism. We found a total of 1096 lncRNAs dysregulated in PDT-treated CRC HCT116 cells; among them, LIFR-AS1 negatively interacted with miR-29a, one of the dysregulated miRNAs in PDT-treated CRC cells, to affect the resistance of CRC to PDT. LIFR-AS1 knockdown attenuated, whereas miR-29a inhibition enhanced the cellular effect of PDT on HCT116 cell proliferation and apoptosis. Furthermore, among the dysregulated mRNAs, TNFAIP3 was confirmed to be a direct target of miR-29a and exerted a similar effect to LIFR-AS1 on the cellular effects of PDT. In summary, LIFR-AS1 serves as a competitive endogenous RNA (ceRNA) for miR-29a to inhibit its expression and up-regulate downstream target TNFAIP3 expression, finally modulating the resistance of CRC to PDT. We provide an experimental basis for this lncRNA/miRNA/mRNA network being a promising target in CRC resistance to PDT treatment.

Yu J, Silva JM
Bayesian Network to Infer Drug-Induced Apoptosis Circuits from Connectivity Map Data.
Methods Mol Biol. 2018; 1783:361-378 [PubMed] Related Publications
The Connectivity Map (CMAP) project profiled human cancer cell lines exposed to a library of anticancer compounds with the goal of connecting cancer with underlying genes and potential treatments. As most targeted anticancer therapeutics aim to induce tumor-selective apoptosis, it is critical to understand the specific cell death pathways triggered by drugs. This can help to better understand the mechanism of how cancer cells respond to chemical stimulations and improve the treatment of human tumors. In this study, using Connectivity MAP microarray-based gene expression data, we applied a Bayesian network modeling approach and identified apoptosis as a major drug-induced cellular pathway. We focused on 13 apoptotic genes that showed significant differential expression across all drug-perturbed samples to reconstruct the apoptosis network. In our predicted subnetwork, 9 out of 15 high-confidence interactions were validated in literature, and our inferred network captured two major cell death pathways by identifying BCL2L11 and PMAIP1 as key interacting players for the intrinsic apoptosis pathway, and TAXBP1 and TNFAIP3 for the extrinsic apoptosis pathway. Our inferred apoptosis network also suggested the role of BCL2L11 and TNFAIP3 as "gateway" genes in the drug-induced intrinsic and extrinsic apoptosis pathways.

Hyeon J, Lee B, Shin SH, et al.
Targeted deep sequencing of gastric marginal zone lymphoma identified alterations of TRAF3 and TNFAIP3 that were mutually exclusive for MALT1 rearrangement.
Mod Pathol. 2018; 31(9):1418-1428 [PubMed] Related Publications
Gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue is a distinct entity in that Helicobacter pylori infection plays the most important causative role in the development of the disease. To investigate the genomic alteration in gastric marginal zone lymphoma that was resistant to the H. pylori eradication therapy, we analyzed 19 cases of the gastric marginal zone lymphoma using fluorescence in situ hybridization for MALT1, BCL10 rearrangement, and targeted sequencing using an Illumina platform. Major genetic alterations affected genes involved in nuclear factor (NF)-κB pathway activation and included MALT1 rearrangement (39%), and somatic mutations of TRAF3 (21%), TNFAIP3 (16%), and NOTCH1 (16%). In the MALT1 rearrangement-negative group, disruptive somatic mutations of TRAF3 were the most common alterations (4/12, 33%), followed by somatic mutations of TNFAIP3 (3/12, 25%), and NOTCH1 (3/12, 25%). The present study confirms that genes involved in activation of NF-κB-signaling pathways are a major driver in oncogenesis of H. pylori eradication-resistant gastric marginal zone lymphoma and revealed that TRAF3 mutation is a major contributor in MALT1 rearrangement-negative gastric marginal zone lymphoma.

Santolla MF, Lappano R, Cirillo F, et al.
miR-221 stimulates breast cancer cells and cancer-associated fibroblasts (CAFs) through selective interference with the A20/c-Rel/CTGF signaling.
J Exp Clin Cancer Res. 2018; 37(1):94 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: MicroRNA (miRNAs) are non-coding small RNA molecules that regulate gene expression by inhibiting the translation of target mRNAs. Among several dysregulated miRNAs in human cancer, the up-regulation of miR-221 has been associated with development of a variety of hematologic and solid malignancies. In this study, we investigated the involvement of miR-221 in breast cancer.
METHODS: TaqMan microRNA assay was used to detect the miR-221 levels in normal cells and in MDA-MB 231 and SkBr3 breast cancer cells as well as in main players of the tumor microenvironment, namely cancer-associated fibroblasts (CAFs). miR-221 mimic sequence and locked nucleic acid (LNA)-i-miR-221 construct were used to induce or inhibit, respectively, the miR-221 expression in cells used. Quantitative PCR and western blotting analysis were performed to evaluate the levels of the miR-221 target gene A20 (TNFAIP3), as well as the member of the NF-kB complex namely c-Rel and the connective tissue growth factor (CTGF). Chromatin immunoprecipitation (ChIP) assay was performed to ascertain the recruitment of c-Rel to the CTFG promoter. Finally, the cell growth and migration in the presence of LNA-i-miR-221 or silencing c-Rel and CTGF by specific short hairpin were assessed by cell count, colony formation and boyden chambers assays. Statistical analysis was performed by ANOVA.
RESULTS: We first demonstrated that LNA-i-miR-221 inhibits both endogenous and ectopic expression of miR-221 in our experimental models. Next, we found that the A20 down-regulation, as well as the up-regulation of c-Rel induced by miR-221 were no longer evident using LNA-i-miR-221. Moreover, we established that the miR-221 dependent recruitment of c-Rel to the NF-kB binding site located within the CTGF promoter region is prevented by using LNA-i-miR-221. Furthermore, we determined that the up-regulation of CTGF mRNA and protein levels by miR-221 is no longer evident using LNA-i-miR221 and silencing c-Rel. Finally, we assessed that cell growth and migration induced by miR-221 in MDA-MB 231 and SkBr3 breast cancer cells as well as in CAFs are abolished by LNAi-miR-221 and silencing c-Rel or CTGF.
CONCLUSIONS: Overall, these data provide novel insights into the stimulatory action of miR-221 in breast cancer cells and CAFs, suggesting that its inhibition may be considered toward targeted therapeutic approaches in breast cancer patients.

Choi J, Lee K, Ingvarsdottir K, et al.
Loss of KLHL6 promotes diffuse large B-cell lymphoma growth and survival by stabilizing the mRNA decay factor roquin2.
Nat Cell Biol. 2018; 20(5):586-596 [PubMed] Free Access to Full Article Related Publications
Kelch-like protein 6 (KLHL6) is an uncharacterized gene mutated in diffuse large B-cell lymphoma (DLBCL). Here we report that KLHL6 assembles with cullin3 to form a functional cullin-RING ubiquitin ligase. Mutations in KLHL6 inhibit its ligase activity by disrupting the interaction with cullin3. Loss of KLHL6 favours DLBCL growth and survival both in vitro and in xenograft models. We further established that the mRNA decay factor roquin2 is a substrate of KLHL6. Degradation of roquin2 is dependent on B-cell receptor activation, and requires the integrity of the Tyr691 residue in roquin2 that is essential for its interaction with KLHL6. A non-degradable roquin2(Y691F) mutant requires its RNA-binding ability to phenocopy the effect of KLHL6 loss. Stabilization of roquin2 promotes mRNA decay of the tumour suppressor and NF-κB pathway inhibitor, tumour necrosis factor-α-inducible gene 3. Collectively, our findings uncover the tumour suppressing mechanism of KLHL6.

Fujii M, Takata K, Chuang SS, et al.
A20 (TNFAIP3) Alterations in Primary Intestinal Diffuse Large B-cell Lymphoma.
Acta Med Okayama. 2018; 72(1):23-30 [PubMed] Related Publications
The gastrointestinal (GI) tract is the most frequently involved site of extranodal non-Hodgkin lymphomas, and diffuse large B-cell lymphoma (DLBCL) is the most common subtype occurring in the GI tract. TNFAIP3 (A20) genetic alterations were reported to be involved in DLBCL's pathogenesis and a portion of GI-DLBCL cases harbor this alteration. However, the frequency and clinicopathological relations focusing on small and large intestinal DLBCL are unclear. Here, we examined A20 deletion and protein expression and analyzed the clinicopathological features of 52 cases of primary intestinal DLBCL. The most frequently involved site was the ileocecal region (75%), followed by small bowel (13.5%) and large intestine. Immunohistochemically, the ileocecal cases expressed BCL6 (p=0.027) and MUM1 (p=0.0001) significantly more frequently than the small intestinal cases. Six of 47 cases (13%) had A20 heterozygous deletion, whereas all 6 heterozygously deleted cases had detectable A20 protein expression. In summary, A20 abnormality was less prevalent among intestinal DLBCLs with some discordancy between gene deletion and protein expression. Although the A20 alteration status did not affect any clinicopathological characteristics in this series, further studies exploring alterations of A20 and other NF-κB components in primary intestinal DLBCL are needed.

Zhao X, Zhang Z, Moreira D, et al.
B Cell Lymphoma Immunotherapy Using TLR9-Targeted Oligonucleotide STAT3 Inhibitors.
Mol Ther. 2018; 26(3):695-707 [PubMed] Free Access to Full Article Related Publications
Growing evidence links the aggressiveness of non-Hodgkin's lymphoma, especially the activated B cell-like type diffuse large B cell lymphomas (ABC-DLBCLs) to Toll-like receptor 9 (TLR9)/MyD88 and STAT3 transcription factor signaling. Here, we describe a dual-function molecule consisting of a clinically relevant TLR9 agonist (CpG7909) and a STAT3 inhibitor in the form of a high-affinity decoy oligodeoxynucleotide (dODN). The CpG-STAT3dODN blocked STAT3 DNA binding and activity, thus reducing expression of downstream target genes, such as MYC and BCL2L1, in human and mouse lymphoma cells. We further demonstrated that injections (i.v.) of CpG-STAT3dODN inhibited growth of human OCI-Ly3 lymphoma in immunodeficient mice. Moreover, systemic CpG-STAT3dODN administration induced complete regression of the syngeneic A20 lymphoma, resulting in long-term survival of immunocompetent mice. Both TLR9 stimulation and concurrent STAT3 inhibition were critical for immune-mediated therapeutic effects, since neither CpG7909 alone nor CpG7909 co-injected with unconjugated STAT3dODN extended mouse survival. The CpG-STAT3dODN induced expression of genes critical to antigen-processing/presentation and Th1 cell activation while suppressing survival signaling. These effects resulted in the generation of lymphoma cell-specific CD8/CD4-dependent T cell immunity protecting mice from tumor rechallenge. Our results suggest that CpG-STAT3dODN as a systemic/local monotherapy or in combination with PD1 blockade can provide an opportunity for treating patients with B cell NHL.

Ahn H, Yang JM, Jeon YK, Paik JH
Clinicopathologic implications of TNFAIP3/A20 deletions in extranodal NK/T-cell lymphoma.
Genes Chromosomes Cancer. 2018; 57(5):231-239 [PubMed] Related Publications
The A20/Tumor necrosis factor-alpha-induced protein 3 (A20/TNFAIP3) is a negative regulator of NF-κB signaling. We analyzed the clinicopathologic implications of A20 deletions in extranodal NK/T-cell lymphoma (NKTL). Fluorescence in situ hybridization analysis of the A20 gene was performed using archived formalin-fixed tissues in 49 cases of NKTL. Among the 49 NKTL patients (median age, 48 y [10-79]), stage I-II (75% [36/48]) and upper aerodigestive tract (UAT)-origin (84% [41/49]) were predominant. All A20 deletions were monoallelic and found in cases with UAT-origin, accounting for 18% (9/49) of all NKTLs and 22% (9/41) of UAT-origin. In univariate analysis, overall survival (OS) and progression-free survival (PFS) were associated with stage, international prognostic index (IPI), B symptoms and number of extranodal sites, and OS with performance status and non-UAT-origin, but none with A20 deletion. In multivariate analysis, IPI predicted OS (P = .008 [HR = 23.4]) and PFS (P = .005 [HR = 34.0]). Risk was divided by B symptoms (P = .001 [OS]; P = .034 [PFS]) in low IPI subset (n = 36), and by A20 deletion (P = .029 [PFS]) in high IPI subset (n = 13). These results suggest a clinicopathologic implication of A20 in progression of NKTL.

Guo T, Zhang Y, Qu X, et al.
miR-200a enhances TRAIL-induced apoptosis in gastric cancer cells by targeting A20.
Cell Biol Int. 2018; 42(5):506-514 [PubMed] Related Publications
Tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) triggers apoptosis by inducing the death-inducing signaling complex (DISC) formation. Recently, TNFα-induced protein 3 (TNFAIP3, A20) was reported to prevent TRAIL-induced caspase 8 cleavage in the DISC by mediating ubiquitination of RIP1 in glioblastoma. However, whether A20 regulates caspase 8 cleavage in the DISC when TRAIL induces apoptosis in gastric cancer cells is unknown. In the present study, A20 interacted with RIP1 and DR4 in MGC803 and SGC7901 gastric cancer cells. Treatment with TRAIL promoted the A20-mediated polyubiquitination of RIP1, caspase 8 translocation into the DISC, and the interaction between caspase 8 and ubiquitinated RIP1. Inhibition of A20 expression prevented the polyubiquitination of RIP1 and promoted caspase 8 cleavage. Moreover, our data clarified that A20 is a target of miR-200a. Overexpression of miR-200a inhibited A20 expression and polyubiquitination of RIP1 and then promoted cleavage of caspase 8 and TRAIL-triggered apoptosis. Taken together, our results indicate that miR-200a enhanced TRAIL-triggered apoptosis in gastric cancer cells by targeting A20.

Yang C, Zang W, Tang Z, et al.
A20/TNFAIP3 Regulates the DNA Damage Response and Mediates Tumor Cell Resistance to DNA-Damaging Therapy.
Cancer Res. 2018; 78(4):1069-1082 [PubMed] Related Publications
A competent DNA damage response (DDR) helps prevent cancer, but once cancer has arisen, DDR can blunt the efficacy of chemotherapy and radiotherapy that cause lethal DNA breakage in cancer cells. Thus, blocking DDR may improve the efficacy of these modalities. Here, we report a new DDR mechanism that interfaces with inflammatory signaling and might be blocked to improve anticancer outcomes. Specifically, we report that the ubiquitin-editing enzyme A20/TNFAIP3 binds and inhibits the E3 ubiquitin ligase RNF168, which is responsible for regulating histone H2A turnover critical for proper DNA repair. A20 induced after DNA damage disrupted RNF168-H2A interaction in a manner independent of its enzymatic activity. Furthermore, it inhibited accumulation of RNF168 and downstream repair protein 53BP1 during DNA repair. A20 was also required for disassembly of RNF168 and 53BP1 from damage sites after repair. Conversely, A20 deletion increased the efficiency of error-prone nonhomologous DNA end-joining and decreased error-free DNA homologous recombination, destablizing the genome and increasing sensitivity to DNA damage. In clinical specimens of invasive breast carcinoma, A20 was widely overexpressed, consistent with its candidacy as a therapeutic target. Taken together, our findings suggest that A20 is critical for proper functioning of the DDR in cancer cells and it establishes a new link between this NFκB-regulated ubiquitin-editing enzyme and the DDR pathway.

Sánchez-Martín D, Otsuka A, Kabashima K, et al.
Effects of DLC1 Deficiency on Endothelial Cell Contact Growth Inhibition and Angiosarcoma Progression.
J Natl Cancer Inst. 2018; 110(4):390-399 [PubMed] Free Access to Full Article Related Publications
Background: Deleted in Liver Cancer 1 (DLC1) is a tumor suppressor gene frequently deleted in cancer. However, DLC1 is not known to be deleted in angiosarcoma, an aggressive malignancy of endothelial cell derivation. Additionally, the physiologic functions of DLC1 protein in endothelial cells are poorly defined.
Methods: We investigated the effects of shRNA-induced DLC1 depletion in endothelial cells. Cell growth was measured by 3H thymidine incorporation, IncuCyte imaging, and population doublings; cell death by cell cycle analysis; gene expression by Affimetrix arrays and quantitative polymerase chain reaction; NF-κB activity by reporter assays; and protein levels by immunoblotting and immunofluorescence staining. We tested Tanespimycin/17-AAG and Fasudil treatment in groups of nine to 10 mice bearing ISOS-1 angiosarcoma. All statistical tests were two-sided.
Results: We discovered that DLC1 is a critical regulator of cell contact inhibition of proliferation in endothelial cells, promoting statistically significant (P < .001) cell death when cells are confluent (mean [SD] % viability: control DLC1 = 15.6 [19.3]; shDLC1 = 73.4 [13.1]). This prosurvival phenotype of DLC1-depleted confluent endothelial cells is attributable to a statistically significant and sustained increase of NF-κB activity (day 5, P = .001; day 8, P = .03) associated with increased tumor necrosis factor alpha-induced protein 3 (TNFAIP3/A20) signaling. Consistently, we found that DLC1 is statistically significantly reduced (P < .001 in 5 of 6) and TNFAIP3/A20 is statistically significantly increased (P < .001 in 2 of 3 and P = 0.02 in 1 of 3) in human angiosarcoma compared with normal adjacent endothelium. Treatment with the NF-κB inhibitor Tanespimycin/17-AAG statistically significantly reduced angiosarcoma tumor growth in mice (treatment tumor weight vs control, 0.50 [0.19] g vs 0.91 [0.21] g, P = .001 experiment 1; 0.66 [0.26] g vs 1.10 [0.31] g, P = .01 experiment 2).
Conclusions: These results identify DLC1 as a previously unrecognized regulator of endothelial cell contact inhibition of proliferation that is depleted in angiosarcoma and support NF-κB targeting for the treatment of angiosarcoma where DLC1 is lost.

Zhou X, An D, Liu X, et al.
TNFα induces tolerant production of CXC chemokines in colorectal cancer HCT116 cells via A20 inhibition of ERK signaling.
Int Immunopharmacol. 2018; 54:296-302 [PubMed] Related Publications
Ubiquitin editing enzyme A20 functions as a tumor suppressor in various cancer. However, the mechanism for A20 regulation of cancer progress is not fully understood. In this study, we found that in human colorectal cancer HCT116 cells, TNFα induced a tolerant production of CXC chemokines, including CXCL1, 2, and 8 in a dose and time dependent manner. TNFα pre-treatment of HCT116 cells down-regulated the chemokine production induced by TNFα re-treatment. TNFα induced the phosphorylation of MAPKs ERK, JNK, P38 and NF-κB P65, but only ERK inhibition decreased TNFα-induced chemokine production. Both RT-PCR and FACS results showed that TNFα treatment did not regulate the expression of TNF receptors. However, TNFα up-regulated the expression of A20 at both mRNA and protein levels significantly. TNFα pre-treatment inhibited the signal transduction of MAPKs induced by TNFα re-stimulation, and A20 over-expression decreased the signal transduction of ERK and P38. Meanwhile, A20 inhibition by RNA interference reversed chemokine down-regulation induced by TNFα re-stimulation after TNFα pre-treatment. Taken together, these results suggested that in human colorectal cancer cells, A20 may function to inhibit cancer progression via down-regulation of TNFα-induced chemokine production by suppression of ERK signaling.

Tian HX, Zhang XC, Yang JJ, et al.
Clinical characteristics and sequence complexity of anaplastic lymphoma kinase gene fusions in Chinese lung cancer patients.
Lung Cancer. 2017; 114:90-95 [PubMed] Related Publications
OBJECTIVES: To investigate the clinical characteristics of anaplastic lymphoma kinase (ALK) rearrangements and sequence complexity of the ALK fusion gene in Chinese lung cancer patients.
METHODS: We prospectively screened ALK rearrangements in 1474 lung cancer specimens, including 1387 cases of non-small cell lung cancer (NSCLC), 54 cases of small cell lung cancer (SCLC), and 33 cases of cancer with lung metastasis from other organs by both standard polymerase chain reaction (PCR) and rapid amplification of cDNA ends (RACE)-coupled PCR. Fifteen cases of ALK-positive RACE-coupled PCR products were transformed into Escherichia coli for molecular cloning and sequenced for complexity analysis.
RESULTS: The overall frequency of ALK rearrangements was 5.1% (71/1387) in NSCLC. In 71 positive cases, the coexistence of epidermal growth factor receptor (EGFR) and ALK variations was found in 6 cases (8.5%), and the coexistence of different ALK variants was found in 2 cases (2.8%) (1 case with variants 1 and 9; the other case with variants 3 and 2) by PCR analysis. Furthermore, through sequence cloning analysis of 15 cases of non-selective ALK-positive samples, two cases with variants 1 and 3 harbored the coexistence of three subtypes (variant 1 subtypes: E13; A20, E13del63; A20 and E7E12E13; A20 and variant 3 subtypes: E6; A20, E6ins33; A20 and E3E6; A20). Variant 3a and 3b subtypes were always coexistent and had the same proportion of ALK variant 3 rearrangements. ALK rearrangement was associated with young age, female gender, never-smokers, those with adenocarcinoma, advanced stage, and EGFR mutations. No ALK fusion was detected in 54 cases of SCLC or 33 cases of cancer with lung metastasis from other organs.
CONCLUSIONS: The identification of novel ALK variants, the coexistence of EGFR mutations and ALK fusions, the coexistence of ALK variants, and the coexistence of subtypes reveal the diversity and sequence complexity of ALK fusions.

Yin L, Fang Z, Shen NJ, et al.
Downregulation of A20 increases the cytotoxicity of IFN-γ in hepatocellular carcinoma cells.
Drug Des Devel Ther. 2017; 11:2841-2850 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC) is a highly fatal disease mandating development of novel, effective therapeutic strategy. Interferon-gamma (IFN-γ) is a pleiotropic cytokine with immunomodulatory, antiviral, and antitumor effects. Although IFN-γ is a promising antitumor agent, its application is limited by resistance in tumor cells. A20 is a zinc-finger protein that was initially identified as a gene product induced by tumor necrosis factor α in human umbilical vein endothelial cells. In this study, we found that silencing of A20 combined with IFN-γ significantly represses cell viability, and induces apoptosis and cell-cycle arrest in HCC cells. By investigating mechanisms implicated in A20 and IFN-γ-mediated signaling pathways, we revealed that the phosphoinositide 3-kinase/Akt signaling pathway and antiapoptotic B-cell lymphoma 2 proteins were repressed. Moreover, we also found that phosphorylation of STAT1 and STAT3 was significantly enhanced after the downregulation of A20 in combination with treatment of IFN-γ. Inhibitor of STAT1 but not STAT3 could block the antitumor effect of IFN-γ. Therefore, targeting A20 enhances the cytotoxicity of IFN-γ against HCC cells and may present a promising therapeutic strategy for HCC.

Varettoni M, Zibellini S, Defrancesco I, et al.
Pattern of somatic mutations in patients with Waldenström macroglobulinemia or IgM monoclonal gammopathy of undetermined significance.
Haematologica. 2017; 102(12):2077-2085 [PubMed] Free Access to Full Article Related Publications
We analyzed

Agathangelidis A, Xochelli A, Stamatopoulos K
A gene is known by the company it keeps: enrichment of TNFAIP3 gene aberrations in MALT lymphomas expressing IGHV4-34 antigen receptors.
J Pathol. 2017; 243(4):403-406 [PubMed] Related Publications
Associations between immunoglobulin (IG) receptors with distinctive immunogenetic features and particular gene mutations are a recurring theme in mature B-cell lymphomas. Relevant observations have been made in chronic lymphocytic leukemia (CLL), where gene mutations are distributed asymmetrically in cases bearing or not somatic hypermutations within the clonotypic immunoglobulin heavy chain variable region (IGHV) genes (e.g. TP53 mutations predominate in IG-unmutated CLL, whereas the opposite is seen for MYD88 mutations, enriched in IG-mutated CLL) and in subsets of cases with stereotyped IG (enrichment for SF3B1 mutations in CLL subset #2). Moreover, similar findings have been reported in splenic marginal-zone lymphoma, where KLF2 mutations are biased to cases expressing IGHV1-2*04 IG receptors, and in hairy cell leukemia, where IGHV4-34-expressing cases display a low frequency of BRAF mutations but a high frequency of MAP2K1 mutations. The list is now growing with the report of increased frequency of inactivating mutations in the TNFAIP3 gene in MALT lymphomas expressing IG receptors encoded by the IGHV4-34 gene, particularly of the ocular adnexa. Considering that TNFAIP3 encodes a negative regulator of NF-κB, this finding further highlights the importance of NF-κB pathway activation in the natural history of MALT lymphomas. Altogether, these findings allude to selection of genomic aberrations in lymphoma cases with distinctive immune signaling profiles linked to the expression of particular IG receptors. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Lee JH, Jung SM, Yang KM, et al.
A20 promotes metastasis of aggressive basal-like breast cancers through multi-monoubiquitylation of Snail1.
Nat Cell Biol. 2017; 19(10):1260-1273 [PubMed] Related Publications
Although the ubiquitin-editing enzyme A20 is a key player in inflammation and autoimmunity, its role in cancer metastasis remains unknown. Here we show that A20 monoubiquitylates Snail1 at three lysine residues and thereby promotes metastasis of aggressive basal-like breast cancers. A20 is significantly upregulated in human basal-like breast cancers and its expression level is inversely correlated with metastasis-free patient survival. A20 facilitates TGF-β1-induced epithelial-mesenchymal transition (EMT) of breast cancer cells through multi-monoubiquitylation of Snail1. Monoubiquitylated Snail1 has reduced affinity for glycogen synthase kinase 3β (GSK3β), and is thus stabilized in the nucleus through decreased phosphorylation. Knockdown of A20 or overexpression of Snail1 with mutation of the monoubiquitylated lysine residues into arginine abolishes lung metastasis in mouse xenograft and orthotopic breast cancer models, indicating that A20 and monoubiquitylated Snail1 are required for metastasis. Our findings uncover an essential role of the A20-Snail1 axis in TGF-β1-induced EMT and metastasis of basal-like breast cancers.

Potenza N, Panella M, Castiello F, et al.
Molecular mechanisms governing microRNA-125a expression in human hepatocellular carcinoma cells.
Sci Rep. 2017; 7(1):10712 [PubMed] Free Access to Full Article Related Publications
MicroRNA-125a-5p (miR-125a) is a vertebrate homolog of lin-4, the first discovered microRNA, and plays a fundamental role in embryo development by downregulating Lin-28 protein. MiR-125a is also expressed in differentiated cells where it generally acts as an antiproliferative factor by targeting membrane receptors or intracellular transductors of mitogenic signals. MiR-125a expression is downregulated in several tumors, including hepatocellular carcinoma (HCC) where it targets sirtuin-7, matrix metalloproteinase-11, VEGF-A, Zbtb7a, and c-Raf. In this study, we have isolated the transcription promoter of human miR-125a and characterized its activity in HCC cells. It is a TATA-less Pol II promoter provided with an initiator element and a downstream promoter element, located 3939 bp upstream the genomic sequence of the miRNA. The activity of the promoter is increased by the transcription factor NF-kB, a master regulator of inflammatory response, and miR-125a itself was found to strengthen this activation through inhibition of TNFAIP3, a negative regulator of NF-kB. This finding contributes to explain the increased levels of miR-125a observed in the liver of patients with chronic hepatitis B.

Jallades L, Baseggio L, Sujobert P, et al.
Exome sequencing identifies recurrent
Haematologica. 2017; 102(10):1758-1766 [PubMed] Free Access to Full Article Related Publications
Splenic diffuse red pulp lymphoma is an indolent small B-cell lymphoma recognized as a provisional entity in the World Health Organization 2008 classification. Its precise relationship to other related splenic B-cell lymphomas with frequent leukemic involvement or other lymphoproliferative disorders remains undetermined. We performed whole-exome sequencing to explore the genetic landscape of ten cases of splenic diffuse red pulp lymphoma using paired tumor and normal samples. A selection of 109 somatic mutations was then evaluated in a cohort including 42 samples of splenic diffuse red pulp lymphoma and compared to those identified in 46 samples of splenic marginal zone lymphoma and eight samples of hairy-cell leukemia. Recurrent mutations or losses in

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