Gene Summary

Gene:TNFRSF1B; TNF receptor superfamily member 1B
Aliases: p75, TBPII, TNFBR, TNFR2, CD120b, TNFR1B, TNFR80, TNF-R75, p75TNFR, TNF-R-II
Summary:The protein encoded by this gene is a member of the TNF-receptor superfamily. This protein and TNF-receptor 1 form a heterocomplex that mediates the recruitment of two anti-apoptotic proteins, c-IAP1 and c-IAP2, which possess E3 ubiquitin ligase activity. The function of IAPs in TNF-receptor signalling is unknown, however, c-IAP1 is thought to potentiate TNF-induced apoptosis by the ubiquitination and degradation of TNF-receptor-associated factor 2, which mediates anti-apoptotic signals. Knockout studies in mice also suggest a role of this protein in protecting neurons from apoptosis by stimulating antioxidative pathways. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:tumor necrosis factor receptor superfamily member 1B
Source:NCBIAccessed: 01 September, 2019


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

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

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: TNFRSF1B (cancer-related)

Wu K, Wang W, Ye Y, et al.
Integration of protein interaction and gene co-expression information for identification of melanoma candidate genes.
Melanoma Res. 2019; 29(2):126-133 [PubMed] Related Publications
Cutaneous melanoma is an aggressive form of skin cancer that causes death worldwide. Although much has been learned about the molecular basis of melanoma genesis and progression, there is also increasing appreciation for the continuing discovery of melanoma genes to improve the genetic understanding of this malignancy. In the present study, melanoma candidate genes were identified by analysis of the common network from cancer type-specific RNA-Seq co-expression data and protein-protein interaction profiles. Then, an integrated network containing the known melanoma-related genes represented as seed genes and the putative genes represented as linker genes was generated using the subnetwork extraction algorithm. According to the network topology property of the putative genes, we selected seven key genes (CREB1, XPO1, SP3, TNFRSF1B, CD40LG, UBR1, and ZNF484) as candidate genes of melanoma. Subsequent analysis showed that six of these genes are melanoma-associated genes and one (ZNF484) is a cancer-associated gene on the basis of the existing literature. A signature comprising these seven key genes was developed and an overall survival analysis of 461 cutaneous melanoma cases was carried out. This seven-gene signature can accurately determine the risk profile for cutaneous melanoma tumors (log-rank P=3.27E-05) and be validated on an independent clinical cohort (log-rank P=0.028). The presented seven genes might serve as candidates for studying the molecular mechanisms and help improve the prognostic risk assessment, which have clinical implications for melanoma patients.

Torrey H, Khodadoust M, Tran L, et al.
Targeted killing of TNFR2-expressing tumor cells and T
Leukemia. 2019; 33(5):1206-1218 [PubMed] Related Publications
Sézary syndrome (SS) is a rare form of cutaneous T-cell lymphoma often refractory to treatment. SS is defined as adenopathy, erythroderma with high numbers of atypical T cells. This offers an opportunity for new interventions and perhaps antibody-based therapeutic by virtue of its high expression of the TNFR2 oncogene on the tumor cells and on T-regulatory cells (T

Wang M, Zhang C, Tian T, et al.
Increased Regulatory T Cells in Peripheral Blood of Acute Myeloid Leukemia Patients Rely on Tumor Necrosis Factor (TNF)-α-TNF Receptor-2 Pathway.
Front Immunol. 2018; 9:1274 [PubMed] Free Access to Full Article Related Publications
Acute myeloid leukemia (AML) harbors an immune suppression environment, featured by increased regulatory T cells (Tregs). The expression of tumor necrosis factor receptor-2 (TNFR2) on Tregs could be used to identify the maximally suppressive Treg population, and TNF-α furtherly promoted the expansion and function of Tregs

Lan X, Sun W, Dong W, et al.
Downregulation of long noncoding RNA H19 contributes to the proliferation and migration of papillary thyroid carcinoma.
Gene. 2018; 646:98-105 [PubMed] Related Publications
Recent studies have highlighted important roles for long noncoding RNAs (lncRNAs) during the complex process of carcinogenesis. H19 is an example of an lncRNA that can function either as a tumor promoter or a tumor suppressor. Here, we investigated the role of H19 in papillary thyroid carcinoma (PTC). First, we assessed H19 expression levels in human PTC tissues and PTC cell lines using quantitative real-time PCR. We also established H19-overexpressed PTC cell lines with lentiviral vectors to investigate the effects of H19 on the proliferation and migration of PTC cells. Our results suggest that H19 is downregulated in PTC tissues and in PTC cell lines compared to controls. Decreased H19 expression was correlated with lymph node metastasis. H19 overexpression reduced PTC cell proliferation and migration. It also inhibited the expression of tumor necrosis factor receptor 2. These results suggest that H19 inhibits tumorigenesis in PTC and may be utilized as a potential diagnostic tool for PTC.

Piltti J, Bygdell J, Qu C, Lammi MJ
Effects of long-term low oxygen tension in human chondrosarcoma cells.
J Cell Biochem. 2018; 119(2):2320-2332 [PubMed] Related Publications
The cell-based therapies could be potential methods to treat damaged cartilage tissues. Instead of native hyaline cartilage, the current therapies generate mainly weaker fibrocartilage-type of repair tissue. A correct microenvironment influences the cellular phenotype, and together with external factors it can be used, for example, to aid the differentiation of mesenchymal stem cells to defined types of differentiated adult cells. In this study, we investigated the effect of long-term exposure to 5% low oxygen atmosphere on human chondrosarcoma HCS-2/8 cells. This atmosphere is close to normal oxygen tension of cartilage tissue. The proteome was analyzed with label-free mass spectrometric method and further bioinformatic analysis. The qRT-PCR method was used to gene expression analysis, and ELISA and dimethylmethylene blue assays for type II collagen and sulfated glycosaminoglycan measurements. The 5% oxygen atmosphere did not influence cell proliferation, but enhanced slightly ACAN and COL2A1 gene expression. Proteomic screening revealed a number of low oxygen-induced protein level responses. Increased ones included NDUFA4L2, P4HA1, NDRG1, MIF, LDHA, PYGL, while TXNRD1, BAG2, TXN2, AQSTM1, TNFRSF1B, and EPHX1 decreased during the long-term low oxygen atmosphere. Also a number of proteins previously not related to low oxygen tension changed during the treatment. Of those S100P, RPSS26, NDUFB11, CDV3, and TUBB8 had elevated levels, while ALCAM, HLA-B, EIF1, and ACOT9 were lower in the samples cultured at low oxygen tension. In conclusion, low oxygen condition causes changes in the cellular amounts of several proteins.

Wang L, Yang D, Tian J, et al.
Tumor necrosis factor receptor 2/AKT and ERK signaling pathways contribute to the switch from fibroblasts to CAFs by progranulin in microenvironment of colorectal cancer.
Oncotarget. 2017; 8(16):26323-26333 [PubMed] Free Access to Full Article Related Publications
Cancer associated fibroblasts (CAFs) are a crucial cellular component in tumor microenvironment and could promote tumor progression. CAFs are usually derived from resident fibroblasts, which undergoing an activated process stimulated by tumor cells. However, the agents and mechanism driving this switch have not yet been elucidated. Progranulin (PGRN), a well acknowledged secreted glycoprotein, could promote proliferation and angiogenesis of colorectal cancer (CRC) cells, and high expression of PGRN correlated with patient poor prognosis. Whether PGRN has effects on the function of stromal fibroblasts is unknown. Herein we found that there was a positive correlation between PGRN expression of CRC cells and expressions of smooth muscle actin α (α-SMA) on CAFs in CRC patient tissues. PGRN/α-SMA co-expression was positively correlated with CRC patient poor prognosis. Co-cultured with CRC cells or human recombinant PGRN (rPGRN), the expression of Ki67, fibroblast activation protein (FAP) and α-SMA in fibroblasts were all up-regulated significantly, accompanying with elevated cellular proliferation, migration and contraction. Whilst co-cultured with PGRN-silenced CRC cells, these functions were down-regulated. Studies of the underlying molecular mechanism demonstrated that either tumor necrosis factor receptor 2 (TNFR2)/Akt or the extracellular regulated kinase (ERK) signaling pathway contributed to modulate of Ki67, FAP, and α-SMA expression, and correlated to abilities of proliferation, migration and contraction in fibroblasts. In conclusion, PGRN plays an important role in activation of CRC fibroblasts, which may be taken as a prospective target of CRC therapy.

Dantas WS, Murai IH, Perandini LA, et al.
Acute exercise elicits differential expression of insulin resistance genes in the skeletal muscle of patients with polycystic ovary syndrome.
Clin Endocrinol (Oxf). 2017; 86(5):688-697 [PubMed] Related Publications
OBJECTIVE: This study aimed to explore the role of acute exercise on skeletal muscle gene expression related to insulin resistance in patients with polycystic ovary syndrome (PCOS) and controls.
METHODS: Four obese women with PCOS and four body mass index (BMI)-matched controls (CTRL) participated in this study. After an overnight fast, the subjects underwent a single 40-min bout of aerobic exercise. Muscle samples were obtained from vastus lateralis at baseline and 60 min after exercise. The expression of a panel of insulin resistance genes was evaluated by a quantitative PCR array system. Network-based analyses were performed to interpret transcriptional changes occurring before and after the exercise challenge.
RESULTS: Overall, differentially expressed genes associated with mitochondria function and peroxisome proliferator-activated receptor signalling were identified. At baseline, there was a significant upregulation of six genes exclusively in PCOS (i.e. NFKBIA, MAPK3, PPARGC1A, GAPDH, ACTB and PPARA). Twelve genes were upregulated in CTRL after a single bout of aerobic exercise (i.e. LEPR, CXCR4, CCR5, IL-18R1, CRLF2, ACACA, CEBPA, PPARGC1A, UCP1, TNFRSF1B, TLR4 and IKBKB). After the exercise session, three genes were upregulated in PCOS (i.e. SOCS3, NAMPT and IL-8), whilst IL-6 was upregulated in both groups after exercise.
CONCLUSIONS: This study provides novel evidence on the effects of acute exercise on insulin resistance genes in skeletal muscle of PCOS. The differentially expressed genes reported herein could be further investigated as targets for therapeutic interventions aimed at improving insulin resistance in this syndrome.

Ba H, Li B, Li X, et al.
Transmembrane tumor necrosis factor-α promotes the recruitment of MDSCs to tumor tissue by upregulating CXCR4 expression via TNFR2.
Int Immunopharmacol. 2017; 44:143-152 [PubMed] Related Publications
Myeloid-derived suppressor cells (MDSCs) accumulated in tumor sites promote immune evasion. We found that TNFR deficiency-induced rejection of transplanted tumor was accompanied with markedly decreased accumulation of MDSCs. However, the mechanism(s) behind this phenomenon is not completely understood. Here, we demonstrated that TNFR deficiency did not affect the amount of MDSCs in bone marrow (BM), but decreased accumulation of Gr-1

Chou CP, Jiang SS, Pan HB, et al.
Endothelial cell colony forming units derived from malignant breast diseases are resistant to tumor necrosis factor-α-induced apoptosis.
Sci Rep. 2016; 6:37450 [PubMed] Free Access to Full Article Related Publications
Mobilisation of endothelial progenitor cells (EPCs) from the bone marrow is a crucial step in the formation of de novo blood vessels, and levels of peripheral blood EPCs have been shown to be elevated in certain malignant states. Using flow cytometry and a Hill-based colony forming unit (CFU) assay, the present study indicated that higher levels of CD34 and vascular endothelial growth factor receptor 2 (VEGFR2) double-positive EPCs, as well as increased formation of endothelial cell colony-forming units (EC-CFUs) are associated with benign and malignant breast diseases, providing possible indicators for breast disease detection. Gene expression profiles revealed a genetic difference between CD34

Cunha R, Zago MA, Querol S, et al.
Impact of CTLA4 genotype and other immune response gene polymorphisms on outcomes after single umbilical cord blood transplantation.
Blood. 2017; 129(4):525-532 [PubMed] Related Publications
We evaluated the impact of recipient and cord blood unit (CBU) genetic polymorphisms related to immune response on outcomes after unrelated cord blood transplantations (CBTs). Pretransplant DNA samples from 696 CBUs with malignant diseases were genotyped for NLRP1, NLRP2, NLRP3, TIRAP/Mal, IL10, REL, TNFRSF1B, and CTLA4. HLA compatibility was 6 of 6 in 10%, 5 of 6 in 39%, and ≥4 of 6 in 51% of transplants. Myeloablative conditioning was used in 80%, and in vivo T-cell depletion in 81%, of cases. The median number of total nucleated cells infused was 3.4 × 10

Wang C, Ma Y, Hu Q, et al.
Bifidobacterial recombinant thymidine kinase-ganciclovir gene therapy system induces FasL and TNFR2 mediated antitumor apoptosis in solid tumors.
BMC Cancer. 2016; 16:545 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Directly targeting therapeutic suicide gene to a solid tumor is a hopeful approach for cancer gene therapy. Treatment of a solid tumor by an effective vector for a suicide gene remains a challenge. Given the lack of effective treatments, we constructed a bifidobacterial recombinant thymidine kinase (BF-rTK) -ganciclovir (GCV) targeting system (BKV) to meet this requirement and to explore antitumor mechanisms.
METHODS: Bifidobacterium (BF) or BF-rTK was injected intratumorally with or without ganciclovir in a human colo320 intestinal xenograft tumor model. The tumor tissues were analyzed using apoptosis antibody arrays, real time PCR and western blot. The colo320 cell was analyzed by the gene silencing method. Autophagy and necroptosis were also detected in colo320 cell. Meanwhile, three human digestive system xenograft tumor models (colorectal cancer colo320, gastric cancer MKN-45 and liver cancer SSMC-7721) and a breast cancer (MDA-MB-231) model were employed to validate the universality of BF-rTK + GCV in solid tumor gene therapy. The survival rate was evaluated in three human cancer models after the BF-rTK + GCV intratumor treatment. The analysis of inflammatory markers (TNF-α) in tumor indicated that BF-rTK + GCV significantly inhibited TNF-α expression.
RESULTS: The results suggested that BF-rTK + GCV induced tumor apoptosis without autophagy and necroptosis occurrence. The apoptosis was transduced by multiple signaling pathways mediated by FasL and TNFR2 and mainly activated the mitochondrial control of apoptosis via Bid and Bim, which was rescued by silencing Bid or/and Bim. However, BF + GCV only induced apoptosis via Fas/FasL signal pathway accompanied with increased P53 expression. We further found that BF-rTK + GCV inhibited the expression of the inflammatory maker of TNF-α. However, BF-rTK + GCV did not result in necroptosis and autophagy.
CONCLUSIONS: BF-rTK + GCV induced tumor apoptosis mediated by FasL and TNFR2 through the mitochondrial control of apoptosis via Bid and Bim without inducing necroptosis and autophagy. Furthermore, BF-rTK + GCV showed to repress the inflammation of tumor through downregulating TNF-α expression. Survival analysis results of multiple cancer models confirmed that BF-rTK + GCV system has a wide field of application in solid tumor gene therapy.

Kurita GP, Ekholm O, Kaasa S, et al.
Genetic variation and cognitive dysfunction in opioid-treated patients with cancer.
Brain Behav. 2016; 6(7):e00471 [PubMed] Free Access to Full Article Related Publications
BACKGROUND AND PURPOSE: The effects of single-nucleotide polymorphisms (SNPs) on the cognitive function of opioid-treated patients with cancer until now have not been explored, but they could potentially be related to poor functioning. This study aimed at identifying associations between SNPs of candidate genes, high opioid dose, and cognitive dysfunction.
METHODS: Cross-sectional multicenter study (European Pharmacogenetic Opioid Study, 2005-2008); 1586 patients; 113 SNPs from 41 genes.
INCLUSION CRITERIA: cancer, age ≥18 year, opioid treatment, and available genetic data. Cognitive assessment by Mini-Mental State Examination (MMSE).
ANALYSES: SNPs were rejected if violation of Hardy-Weinberg equilibrium (P < 0.0005), or minor allele frequency <5%; patients were randomly divided into discovery sample (2/3 for screening) and validation sample (1/3 for confirmatory test); false discovery rate of 10% for determining associations (Benjamini-Hochberg method). Co-dominant, dominant, and recessive models were analyzed by Kruskal-Wallis and Mann-Whitney tests.
RESULTS: In the co-dominant model significant associations (P < 0.05) between MMSE scores and SNPs in the HTR3E,TACR1, and IL6 were observed in the discovery sample, but the replication in the validation sample did not confirm it. Associations between MMSE scores among patients receiving ≥400 mg morphine equivalent dose/day and SNPs in TNFRSF1B,TLR5,HTR2A, and ADRA2A were observed, but they could not be confirmed in the validation sample. After correction for multiple testing, no SNPs were significant in the discovery sample. Dominant and recessive models also did not confirm significant associations.
CONCLUSIONS: The findings did not support influence of those SNPs analyzed to explain cognitive dysfunction in opioid-treated patients with cancer.

Singhal P, Sharma U, Hussain S, et al.
Identification of genetic variants in TNF receptor 2 which are associated with the development of cervical carcinoma.
Biomarkers. 2016; 21(7):665-72 [PubMed] Related Publications
Cervical cancer is one of the most common malignancies among women in India. Beside HPV, other factors present in host also put their role in the progression of cervical tumerogenesis. In present study, we screened 300 subjects to identify variations in TNFR2 gene by PCR-dHPLC method followed by direct sequencing. We identified six known and four novel variations in six different exons of TNFR2 gene. Out of these identified variations, five known variations were found to be significantly associated with the risk of cervical cancer (p < 0.0001). On construction of haplotypes, one haplotype (TTGCC) was emerged as a major protective type while two (CAAGC + CTGCC) were revealed as major risk haplotypes. In conclusion, postmenopausal women having CAAGC + CTGCC haplotypes in TNFR2 gene along with HPV infection and tobacco consumption may lead to the development of cervical cancer.

Stachura A, Brym P, Bojarojć-Nosowicz B, Kaczmarczyk E
Polymorphism and expression of the tumor necrosis factor receptor II gene in cows infected with the bovine leukemia virus.
Pol J Vet Sci. 2016; 19(1):125-31 [PubMed] Related Publications
A single T>C nucleotide polymorphism (rs42686850) of bovine tumor necrosis factor receptor type II gene (TNF-RII) is located within a sequence with allele-specific affinity to bind E2F transcription factors, considered pivotal in the regulation of cell cycle and cell proliferation. The objective of the study was to determine the effect of this SNP and BLV infection on the TNF-RII gene expression at the mRNA and protein levels in peripheral blood mononuclear cells (PBMC). We noted that analyzed TNF-RII gene polymorphism influenced the expression of the TNF-RII gene at the mRNA level but only in BLV-positive cows. Concurrently, no statistically significant association was found between gene polymorphism and TNF-RII expression at the protein level. However, we found a significant effect of BLV infection status on the amount of TNF-RII mRNA and the percentage of PBMC expressing TNF-RII. These results show an unclear effect of considered T>C polymorphism on TNF-RII gene expression in bovine leukocytes and they suggest the involvement of BLV in modifying the TNF-RII expression in BLV-infected cows potentially implying the EBL (Enzootic Bovine Leukosis) associated pathogenesis.

Cui H, Liu J, Li L, et al.
Analysis of differential β variable region of T cell receptor expression and NAV3/TNFRSF1B gene mutation in mycosis fungoides.
Oncotarget. 2016; 7(14):17986-90 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: This study aimed to analyze the predominant expression of the variable region of T cell receptor (TRBV) and determine whether NAV3 or TNFRSF1B gene mutation involved in the pathogenesis of MF.
RESULTS: TRBV5-7 expression increased from the normal, early-stage to advanced-stage lesion in MF patient. By contrast, TRBV2 decreased with the lesion developed. We found no mutations of NAV3 or TNFRSF1B in the lesions from this study.
MATERIALS AND METHODS: Real-time PCR were used to screen differential expression of TRBV in different lesions. Mutational analyses were used to validate genetic alterations in the skin lesions.
CONCLUSIONS: The identification of TRBV gene expression differences between normal and different stages of MF lesions provide insight into promising new diagnostic and prognostic biomarkers. None of the reported genetic abnormalities suggests complexity of progress from a primary cytogenetic event to an advanced stage with poor prognosis in MF.

Nagaishi T, Watabe T, Jose N, et al.
Epithelial Nuclear Factor-x03BA;B Activation in Inflammatory Bowel Diseases and Colitis-Associated Carcinogenesis.
Digestion. 2016; 93(1):40-6 [PubMed] Related Publications
Prolonged inflammatory bowel diseases (IBD) may lead to colitis-associated carcinogenesis (CAC). Previous studies had shown that nuclear factor-x03BA;B (NF-x03BA;B) activation in both macrophages and epithelia in inflamed colonic tissue is associated with CAC development. However, the mechanism by which epithelial NF-x03BA;B activation leading to CAC development had not previously been rigorously studied. We and others had observed the increased expression of the type 2 receptor for tumor necrosis factor (TNFR2/TNFRSF1b/p75) in IBD models. Myosin light chain kinase (MLCK) is suggested to be associated with epithelial permeability via TNF signaling. Therefore, the relationship between epithelial MLCK expression and NF-x03BA;B activation via TNFR2 signaling on CAC development was investigated. Pro-tumorigenic cytokines such as interleukin (IL)-1β, IL-6 and macrophage inflammatory protein-2 at the lamina propria were increased in the setting of colitis and further increased in tumor tissues with upregulated epithelial TNFR2 and MLCK expressions in an animal model of CAC. The upregulated MLCK expression was also observed in TNF-stimulated colonic epithelial cells in vitro in association with the upregulation of TNFR2 but not TNFR1/TNFRSF1a/p55. Gene silencing of tnfrsf1b, but not tnfrsf1a, resulted in restoration of epithelial tight junction (TJ) associated with decreased MLCK expression. The presence of anti-TNF antibody also resulted in restoration of TJ in association with suppressed MLCK expression, and interestingly, similar results including the suppressed TNFR2 and MLCK expressions were observed by inhibiting MLCK in the epithelial cells. MLCK silencing also led to suppressed TNFR2 expression, suggesting that the restored TJ leads to reduced TNFR2 signaling. Such suppression of MLCK as well as blockade of TNFR2 signaling resulted in reduced CAC development, restored TJ, and decreased pro-tumorigenic cytokines. These imply that TNF-induced NF-x03BA;B activation and MLCK expression may be a potential target for the prevention of IBD-associated carcinogenesis.

Ungewickell A, Bhaduri A, Rios E, et al.
Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2.
Nat Genet. 2015; 47(9):1056-60 [PubMed] Free Access to Full Article Related Publications
Mycosis fungoides and Sézary syndrome comprise the majority of cutaneous T cell lymphomas (CTCLs), disorders notable for their clinical heterogeneity that can present in skin or peripheral blood. Effective treatment options for CTCL are limited, and the genetic basis of these T cell lymphomas remains incompletely characterized. Here we report recurrent point mutations and genomic gains of TNFRSF1B, encoding the tumor necrosis factor receptor TNFR2, in 18% of patients with mycosis fungoides and Sézary syndrome. Expression of the recurrent TNFR2 Thr377Ile mutant in T cells leads to enhanced non-canonical NF-κB signaling that is sensitive to the proteasome inhibitor bortezomib. Using an integrative genomic approach, we additionally discovered a recurrent CTLA4-CD28 fusion, as well as mutations in downstream signaling mediators of these receptors.

Ma X, Li X, Lu X, et al.
Interaction between TNFR1 and TNFR2 dominates the clinicopathologic features of human hypopharyneal carcinoma.
Tumour Biol. 2015; 36(12):9421-9 [PubMed] Related Publications
Although the expression of tumor necrosis factor receptors (TNFRs) has been associated with clinicopathologic features of some other cancers, their roles in hypopharyngeal squamous cell carcinoma (HPSCC) have not been documented. Forty-five HPSCC specimens were analyzed for the expression of TNFR1 and TNFR2 and its relationship with clinicopathologic factors. Interaction between the two receptors and its effects on TNF-α was investigated by neutralizing TNFR1 and upregulation of TNFR2. The results indicated that, in HPSCC specimens, the expression of TNFR1 but not TNFR2 is associated with clinical staging, T stage, cervical lymph node metastasis, and histologic grade in HPSCC. In Fadu cells, when conjugating with its receptors, TNF-α mediates proliferation effects, and neutralizing TNFR1 and/or upregulating TNFR2 evokes proliferation-inhibiting and apoptosis-inducing effects and potentiates cisplatin (DDP)-induced growth inhibition and apoptosis induction. In conclusion, interaction of TNFR1 with TNFR2 determines the biological characters of HPSCC, and TNFR1 may dominate this process. Moreover, interaction between the two receptors plays important roles in determining the fates of HPSCC cells and thus may serve as a therapeutic target for developing new therapeutic strategies for HPSCC.

Sghaier I, Zidi S, Mouelhi L, et al.
The relationship between TNF alpha gene polymorphisms (-238/-308), TNF RII VNTR (p75) and outcomes of hepatitis B virus infection in Tunisian population.
Gene. 2015; 568(2):140-5 [PubMed] Related Publications
The present study was undertaken to investigate the association between Hepatitis B Virus (HBV) infection and polymorphisms of tumour necrosis factor alpha TNF-α -308 G>A, TNF-α -238 G>A and TNF RII VNTR (p75) gene promoter in a Tunisian population. Blood samples were collected from 100 Tunisian patients with HBV infection, 45 with Chronic Hepatitis (CH), 36 with Liver Cirrhosis (LC), 15 with Hepatocellular Carcinoma (HCC) and 200 healthy individuals of similar ethnicity. Genomic DNA was extracted from peripheral blood leukocytes. Genotyping of the analysed polymorphisms was performed using Amplified Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR), Restriction Fragment Length Polymorphism (RFLP) and Variable Number Tandem Repeat PCR (PCR-VNTR). The variant homozygotes -308 GG were associated with 50% decreased risk of HBV chronic infection (GG vs AA+GA; p=0.010; OR=0.50; 95%CI=0.29-0.85). However, the carriers of minor allele -308 A have higher risk (1.5 times) to develop a chronic infection than other patients (p=0.027; OR=1.46; 95%CI=1.04-2.06). The minor allele of -238 polymorphism was positively associated with virus resistance and the development of chronic infection (p=0.043; OR=1.42; 95%CI =1.01 1.99). The distribution of -308, -238 and TNF RII VNTR (p75) among the three groups differed significantly. For HCC groups, there were statistically significant differences in allele distribution in -308, -238 respectively in which A allele remains a risk factor for HBV evolution to HCC (p=0.008 and p=0.026). Haplotype analysis revealed that TNF-α (-308A; -238A) was significantly associated to HBV chronic infection and moreover to disease aggravation to HCC stage. Our findings imply that variations in the genes governing the levels of constitutive and inducible TNF-α and TNF RII might be an important risk factor, which could explain the variable outcomes of HBV infection.

Lauenborg B, Christensen L, Ralfkiaer U, et al.
Malignant T cells express lymphotoxin α and drive endothelial activation in cutaneous T cell lymphoma.
Oncotarget. 2015; 6(17):15235-49 [PubMed] Free Access to Full Article Related Publications
Lymphotoxin α (LTα) plays a key role in the formation of lymphatic vasculature and secondary lymphoid structures. Cutaneous T cell lymphoma (CTCL) is the most common primary lymphoma of the skin and in advanced stages, malignant T cells spreads through the lymphatic to regional lymph nodes to internal organs and blood. Yet, little is known about the mechanism of the CTCL dissemination. Here, we show that CTCL cells express LTα in situ and that LTα expression is driven by aberrantly activated JAK3/STAT5 pathway. Importantly, via TNF receptor 2, LTα functions as an autocrine factor by stimulating expression of IL-6 in the malignant cells. LTα and IL-6, together with VEGF promote angiogenesis by inducing endothelial cell sprouting and tube formation. Thus, we propose that LTα plays a role in malignant angiogenesis and disease progression in CTCL and may serve as a therapeutic target in this disease.

Mahalingam J, Lin CY, Chiang JM, et al.
CD4⁺ T cells expressing latency-associated peptide and Foxp3 are an activated subgroup of regulatory T cells enriched in patients with colorectal cancer.
PLoS One. 2014; 9(9):e108554 [PubMed] Free Access to Full Article Related Publications
Latency-associated peptide (LAP) - expressing regulatory T cells (Tregs) are important for immunological self-tolerance and immune homeostasis. In order to investigate the role of LAP in human CD4⁺Foxp3⁺ Tregs, we designed a cross-sectional study that involved 42 colorectal cancer (CRC) patients. The phenotypes, cytokine-release patterns, and suppressive ability of Tregs isolated from peripheral blood and tumor tissues were analyzed. We found that the population of LAP-positive CD4⁺Foxp3⁺ Tregs significantly increased in peripheral blood and cancer tissues of CRC patients as compared to that in the peripheral blood and tissues of healthy subjects. Both LAP⁺ and LAP⁻ Tregs had a similar effector/memory phenotype. However, LAP⁺ Tregs expressed more effector molecules, including tumor necrosis factor receptor II, granzyme B, perforin, Ki67, and CCR5, than their LAP⁻ negative counterparts. The in vitro immunosuppressive activity of LAP⁺ Tregs, exerted via a transforming growth factor-β-mediated mechanism, was more potent than that of LAP⁻ Tregs. Furthermore, the enrichment of LAP⁺ Treg population in peripheral blood mononuclear cells (PBMCs) of CRC patients correlated with cancer metastases. In conclusion, we found that LAP⁺ Foxp3⁺ CD4⁺ Treg cells represented an activated subgroup of Tregs having more potent regulatory activity in CRC patients. The increased frequency of LAP⁺ Tregs in PBMCs of CRC patients suggests their potential role in controlling immune response to cancer and presents LAP as a marker of tumor-specific Tregs in CRC patients.

Zidi S, Stayoussef M, Zouidi F, et al.
Tumor Necrosis Factor Alpha (-238 / -308) and TNFRII-VNTR (-322) Polymorphisms as Genetic Biomarkers of Susceptibility to Develop Cervical Cancer Among Tunisians.
Pathol Oncol Res. 2015; 21(2):339-45 [PubMed] Related Publications
Host genetic factors may confer susceptibility to Cervical Cancer. TNF-α as pro-inflammatory cytokine participates in the maintenance of immune homeostasis. Allelic variation of immuno-modulatory genes is associated with alteration in immune function. This study investigated the associations between TNF-α-308G>A, -238G>A, and TNFRII - VNTR-322 and cervical cancer in Tunisian women. Genotypes of those polymorphisms were detected in 130 cases and 260 controls. The variant heterozygote -308 G/A was associated with a 41% decreased risk of cervical cancer (GG vs A/A; p = 0.002; OR = 0.41; 95% CI =0.23-0.76). Furthermore, compared with dominant variant G/G, the (G/A+A/A) genotypes was significantly associated with a decreased risk of CC (GG vs G/A+A/A; p = 0.026; OR = 0.62; 95% CI = 0.40-0.97). The FIGO stratified analysis showed that the minor variant A/A and combined G/A+A/A of TNFα-238 G>A and TNFα-308 G>A increased the risk of the tumor evolution, respectively, (P = 0.011; OR = 2.98; 95% CI = 1.16-7.72) (P = 0.008; OR = 2.76; 95% CI = 1.20-6.41), (P = 0.000; OR = 16.33; 95% CI = (5.10-55.23) (P = 0.000; OR = 7.54; 95% CI = 2.68-22.29). There was statistically significant relationship between the incidence of the TNF-α mutations and the clinical progression of cancer according to the FIGO classification. In our study, the haploview analysis revealed no LD between rs1800629 and rs361525. TNF-α and TNFRII polymorphisms might be genetic risk factors for cervical cancer in Tunisian population.

Wu JH, Yao YL, Gu T, et al.
MiR-421 regulates apoptosis of BGC-823 gastric cancer cells by targeting caspase-3.
Asian Pac J Cancer Prev. 2014; 15(13):5463-8 [PubMed] Related Publications
MicroRNAs might act as oncogenes or tumor suppressors in cancer. Recent studies have shown that miR-421 is up-regulated in human gastric cancer. Here, we found that miR-421 was over-expressed in gastric cancer tissues and cell lines. Bioinformatics analysis predicted that the caspase-3 gene was a target of miR-421. Caspase-3 was negatively regulated by miR-421 at the post-transcriptional level. Bax and Bcl-2 were also regulated by miR-421. Moreover, tumor necrosis factor receptor-I and -II, death receptors in the apoptosis pathway, were up-regulated by miR-421. The over-expression of miR-421 promoted gastric cancer cell growth and inhibited apoptosis of the BGC-823 gastric cancer cell line. These observations indicate that miR-421 acts as a tumor promoter by targeting the caspase-3 gene and preventing apoptosis of gastric cancer cells through inhibition of caspase-3 expression. These findings contribute to our understanding of the functions of miR-421 in gastric cancer.

Nakayama S, Yokote T, Tsuji M, et al.
Expression of tumour necrosis factor-α and its receptors in Hodgkin lymphoma.
Br J Haematol. 2014; 167(4):574-7 [PubMed] Related Publications

Xu F, Zhou G, Han S, et al.
Association of TNF-α, TNFRSF1A and TNFRSF1B gene polymorphisms with the risk of sporadic breast cancer in northeast Chinese Han women.
PLoS One. 2014; 9(7):e101138 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The interaction of tumor necrosis factor-α (TNF-α) with its receptors: TNFRSF1A and TNFRSF1B is critical for the promotion of tumor growth, invasion and metastasis. To better understand the roles of single nucleotide polymorphisms (SNPs) in the TNF-α, TNFRSF1A and TNFRSF1B genes in the development of breast cancer, we explored the associations between SNPs in these three genes and breast cancer susceptibility in northeast Chinese Han women.
METHODOLOGY/PRINCIPAL FINDINGS: This case-control study was conducted among 1016 breast cancer patients and 806 age-matched healthy controls. Seven SNPs in the TNF-α (rs1800629, rs361525), TNFRSF1A (rs767455, rs4149577 and rs1800693) and TNFRSF1B (rs1061622 and rs1061624) genes were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. In TNFRSF1B, the rs1061622 GT genotype and the G allele conferred a reduced susceptibility to breast cancer (P = 0.000662, OR = 0.706, 95% CI: 0.578-0.863; P = 0.002, OR = 0.769, 95% CI; 0.654-0.905, respectively). Moreover, the AG genotype, the AA genotype and the A allele in rs1061624 conferred an increased risk of breast cancer (P = 0.007, OR = 1.470, 95% CI:1.112-1.943; P = 0.00109, OR = 1.405 95% CI:1.145-1.724; P = 0.001, OR = 1.248 95% CI:1.092-1.426, respectively). These two SNPs also had associations with breast cancer risk under the dominant model. In haplotype analysis, the CTA (rs767455 C-rs4149577 T-rs1800693 A) haplotype in TNFRSF1A and the TA (rs1061622 T-rs1061624 A) haplotype in TNFRSF1B had higher frequencies in breast cancer patients (P = 0.00324; P = 0.000370, respectively), but the frequency of GG (rs1061622 G-rs1061624 G) haplotype in TNFRSF1B was lower in breast cancer patients (P = 0.000251). The associations of the three haplotypes remained significant after correcting for multiple testing. In addition, significant associations were also observed between TNFRSF1A polymorphisms and lymph node metastasis, P53, estrogen receptor (ER) and progesterone receptor (PR) statuses.
CONCLUSIONS: Our results suggest that rs1061622 and rs1061624 in TNFRSF1B may affect breast cancer risk, and SNPs in TNFRSF1A are associated with the clinical features of breast cancer.

Yu Y, Zheng S, Zhang S, et al.
Polymorphisms of inflammation-related genes and colorectal cancer risk: a population-based case-control study in China.
Int J Immunogenet. 2014; 41(4):289-97 [PubMed] Related Publications
The previous studies found that chronic inflammation related to an increased risk of colorectal cancer (CRC). This study aims to explore the associations of polymorphisms in inflammation-related genes (IL10, IL10RA, IL6R, TNFRSF1A, TNFRSF1B, LTA and IL4) and their interactions with the risk of colorectal cancer among Chinese population. A population-based case-control study including 299 cases and 296 controls was conducted from January 2001 to December 2009. Multivariate unconditional logistic regression was used to analyse the association of nine SNPs in inflammation-related genes with the risk of CRC, colon cancer and rectal cancer, respectively. Generalized multifactor dimensionality reduction (GMDR) was implemented to explore the gene-gene interactions among all SNPs on CRC. A decreased risk of colorectal cancer in subjects with rs1800872 AC genotype of IL10 (OR = 0.643, 95%CI = 0.453, 0.912) or AC/CC genotype (OR = 0.636, 95%CI = 0.457, 0.885) was observed, compared with those with AA genotype. Meanwhile, similar associations were observed between rs1800872 and rectal cancer. Additionally, in rs1061624 of TNFRSF1B gene, AG genotype (OR=0.566; 95% CI= 0.362, 0.885) and AG/GG genotype (OR=0.638; 95% CI=0.420, 0.971) were significantly associated with a decreased risk of rectal cancer, respectively. Our findings indicated that mutants in IL10 and TNFRSF1B genes may change the CRC risk. However, there is no interaction between inflammation-related genes on CRC risk.

Govindaraj C, Madondo M, Kong YY, et al.
Lenalidomide-based maintenance therapy reduces TNF receptor 2 on CD4 T cells and enhances immune effector function in acute myeloid leukemia patients.
Am J Hematol. 2014; 89(8):795-802 [PubMed] Related Publications
A major limitation to improved outcomes in acute myelogenous leukemia (AML) is relapse resulting from leukemic cells that persist at clinical remission. Regulatory T cells (Tregs), which are increased in AML patients, can contribute to immune evasion by residual leukemic cells. Tumor necrosis factor (TNF), a pro-inflammatory cytokine present at high levels within patients, can induce TNF receptor-2 (TNFR2) expression on Tregs. We hypothesized that since TNFR2 is required for Treg stabilization and TNFR2+ Tregs are potent suppressors, targeting TNFR2+ Tregs may restore the effectiveness of immune-surveillance mechanisms. In this pilot study, we report AML patients in clinical remission have substantially increased levels of TNFR2+ T cells, including TNFR2+ Tregs and impaired effector CD4 T cell function with reduced IL-2 and IFNγ production. The immunomodulatory drug, lenalidomide, and the demethylating agent, azacitidine have been moderately successful in treating AML patients, but their combined effects on TNFR2+ T cells, including Tregs are currently unknown. Our data indicates that although treatment with lenalidomide and azacitidine increased cytokine production by effector T cells in all patients, durable clinical remissions may be observed in patients with a concomitant reduction in TNFR2+ T cells and TNFR2+ Tregs. In vitro studies further demonstrated that lenalidomide can reduce TNFR2 expression and can augment effector cytokine production by T cells, which can be further enhanced by azacitidine. These results indicate that reduction of TNFR2+ T cells in AML postremission phase may result from combined azacitidine/lenalidomide therapy and may contribute to an improved clinical outcome.

Peng DF, Hu TL, Soutto M, et al.
Loss of glutathione peroxidase 7 promotes TNF-α-induced NF-κB activation in Barrett's carcinogenesis.
Carcinogenesis. 2014; 35(7):1620-8 [PubMed] Free Access to Full Article Related Publications
Esophageal adenocarcinoma (EAC) is a classic example of inflammation-associated cancer, which develops through GERD (gastroesophageal reflux disease)-Barrett's esophagus (BE)-dysplasia-adenocarcinoma sequence. The incidence of EAC has been rising rapidly in the USA and Western countries during the last few decades. The functions of glutathione peroxidase 7 (GPX7), an antioxidant enzyme frequently silenced during Barrett's tumorigenesis, remain largely uncharacterized. In this study, we investigated the potential role of GPX7 in regulating nuclear factor-kappaB (NF-κB) activity in esophageal cells. Western blot analysis, immunofluorescence and luciferase reporter assay data indicated that reconstitution of GPX7 expression in CP-A (non-dysplastic BE cells) and FLO-1 (EAC cells) abrogated tumor necrosis factor-α (TNF-α)-induced NF-κB transcriptional activity (P < 0.01) and nuclear translocation of NF-κB-p65 (P = 0.01). In addition, we detected a marked reduction in phosphorylation levels of components of NF-κB signaling pathway, p-p65 (S536), p-IκB-α (S32) and p-IKKα/β (S176/180), as well as significant suppression in induction of NF-κB target genes [TNF-α, interleukin (IL)-6, IL-8, IL-1β, CXCL-1 and CXCL-2] following treatment with TNF-α in GPX7-expressing FLO-1 cells as compared with control cells. We validated these effects by knockdown of GPX7 expression in HET1A (normal esophageal squamous cells). We found that GPX7-mediated suppression of NF-κB is independent of reactive oxygen species level and GPX7 antioxidant function. Further mechanistic investigations demonstrated that GPX7 promotes protein degradation of TNF-receptor 1 (TNFR1) and TNF receptor-associated factor 2 (TRAF2), suggesting that GPX7 modulates critical upstream regulators of NF-κB. We concluded that the loss of GPX7 expression is a critical step in promoting the TNF-α-induced activation of proinflammatory NF-κB signaling, a major player in GERD-associated Barrett's carcinogenesis.

Sasi SP, Bae S, Song J, et al.
Therapeutic non-toxic doses of TNF induce significant regression in TNFR2-p75 knockdown Lewis lung carcinoma tumor implants.
PLoS One. 2014; 9(3):e92373 [PubMed] Free Access to Full Article Related Publications
Tumor necrosis factor-alpha (TNF) binds to two receptors: TNFR1/p55-cytotoxic and TNFR2/p75-pro-survival. We have shown that tumor growth in p75 knockout (KO) mice was decreased more than 2-fold in Lewis lung carcinoma (LLCs). We hypothesized that selective blocking of TNFR2/p75 LLCs may sensitize them to TNF-induced apoptosis and affect the tumor growth. We implanted intact and p75 knockdown (KD)-LLCs (>90%, using shRNA) into wild type (WT) mice flanks. On day 8 post-inoculation, recombinant murine (rm) TNF-α (12.5 ng/gr of body weight) or saline was injected twice daily for 6 days. Tumor volumes (tV) were measured daily and tumor weights (tW) on day 15, when study was terminated due to large tumors in LLC+TNF group. Tubular bones, spleens and peripheral blood (PB) were examined to determine possible TNF toxicity. There was no significant difference in tV or tW between LLC minus (-) TNF and p75KD/LLC-TNF tumors. Compared to 3 control groups, p75KD/LLC+TNF showed >2-5-fold decreases in tV (p<0.001) and tW (p<0.0001). There was no difference in tV or tW end of study vs. before injections in p75KD/LLC+TNF group. In 3 other groups tV and tW were increased 2.7-4.5-fold (p<0.01, p<0.0002 and p<0.0001). Pathological examination revealed that 1/3 of p75KD/LLC+rmTNF tumors were 100% necrotic, the remaining revealed 40-60% necrosis. No toxicity was detected in bone marrow, spleen and peripheral blood. We concluded that blocking TNFR2/p75 in LLCs combined with intra-tumoral rmTNF injections inhibit LLC tumor growth. This could represent a novel and effective therapy against lung neoplasms and a new paradigm in cancer therapeutics.

Galatola M, Miele E, Strisciuglio C, et al.
Synergistic effect of interleukin-10-receptor variants in a case of early-onset ulcerative colitis.
World J Gastroenterol. 2013; 19(46):8659-70 [PubMed] Free Access to Full Article Related Publications
AIM: To investigated the molecular cause of very early-onset ulcerative colitis (UC) in an 18-mo-old affected child.
METHODS: We analysed the interleukin-10 (IL10) receptor genes at the DNA and RNA level in the proband and his relatives. Beta catenin and tumor necrosis factor-α (TNFα) receptors were analysed in the proteins extracted from peripheral blood cells of the proband, his relatives and familial adenomatous polyposis (FAP) and PTEN hamartoma tumor syndrome (PHTS) patients. Samples were also collected from the proband's inflamed colorectal mucosa and compared to healthy and tumour mucosa collected from a FAP patient and patients affected by sporadic colorectal cancer (CRC). Finally, we examined mesalazine and azathioprine effects on primary fibroblasts stabilised from UC and FAP patients.
RESULTS: Our patient was a compound heterozygote for the IL10RB E47K polymorphism, inherited from his father, and for a novel point mutation within the IL10RA promoter (the -413G->T), inherited from his mother. Beta catenin and tumour necrosis factor α receptors-I (TNFRI) protein were both over-expressed in peripheral blood cells of the proband's relatives more than the proband. However, TNFRII was over-expressed only in the proband. Finally, both TNFα-receptors were shown to be under-expressed in the inflamed colon mucosa and colorectal cancer tissue compared to healthy colon mucosa. Consistent with this observation, mesalazine and azathioprine induced, in primary fibroblasts, IL10RB and TNFRII over-expression and TNFRI and TNFα under-expression. We suggest that β-catenin and TNFRI protein expression in peripheral blood cells could represent molecular markers of sub-clinical disease in apparently healthy relatives of patients with early-onset UC.
CONCLUSION: A synergistic effect of several variant alleles of the IL10 receptor genes, inherited in a Mendelian manner, is involved in UC onset in this young child.

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