This gene belongs to the tumor necrosis factor receptor superfamily. The encoded protein is postulated to play a regulatory role in suppressing FasL- and LIGHT-mediated cell death. It acts as a decoy receptor that competes with death receptors for ligand binding. Over-expression of this gene has been noted in gastrointestinal tract tumors. Read-through transcription into this gene from the neighboring upstream gene, which encodes regulator of telomere elongation helicase 1 (RTEL1), generates a non-coding transcript. [provided by RefSeq, Feb 2011]
TNFRSF6B gene amplification and overexpression of the TNFRSF6B protein have been demonstrated in a range of different types of cancers (some listed below) and found to be a prognostic factor and linked to chemotherapy resistance in some studies.
FASL and FAS mediate immune-cytotoxic killing of virus-infected, cancer and other potentially harmful cells. Pitti et al (1998) demonstrated that TNFRSF6B (DCR3) binds to FASL and inhibits FASL-induced apoptosis. They found TNFRSF6B gene amplification (multiple copies) in about half of cases from an analysis of 35 primary lung and colon tumours. They hypothesized that, cancer cells may escape FASL-dependent immune-cytotoxic attack by expressing this 'decoy' receptor which blocks FASL.
TNFRSF6B Amplification and Overexpression in Gastric CancersPrognostic Bai et al (2000) found TNFRSF6B protein was overexpressed in 30 of 68 (44%) human adenocarcinomas of the esophagus, stomach, colon, and rectum. In many cases overexpression occurred in tumors in which gene amplification could not be detected by FISH. Takahama et al (2002) reported overexpression of TNFRSF6B in 26% of 84 gastric cancer surgical specimens and expression level was significantly associated with lymph node metastasis, pathological stage, and survival. In a high resolution analysis of DNA copy-number aberrations in gastric cancer
Buffart et al (2009) found DNA copy-number gains of TNFRSF6B and ZNF217 (20q13.2) were significantly associated with lymph node metastasis and histological type.
TNFRSF6B expression and Drug Resistance Some studies have linked TNFRSF6B expression to chemotherapy efficacy / resistance. For example: Mild et al. (2002) found 5-fluorouracil-based adjuvant chemotherapy was significantly more beneficial in colorectal cancer patients with normal DcR3 gene copy number than in patients with amplification. In an in vitro study Chang et al(2008) found that neutralization of DcR3 increased the percentage of doxorubicin-mediated apoptosis in two B-cell lymphoma cell lines, ans suggested that DcR3 mediated chemo-resistance in B-cell lymphomas. Connor et al (2012) reported that DcR3 binds to ovarian cancer via heparan sulfate proteoglycans and modulates tumor cells response to platinum with corresponding alteration in the expression of BRCA1.
Atlas of Genetics and Cytogenetics in Oncology and Haematology
TNFRSF6B OMIM, Johns Hopkin University Referenced article focusing on the relationship between phenotype and genotype.
TNFRSF6B International Cancer Genome Consortium. Summary of gene and mutations by cancer type from ICGC
TNFRSF6B Cancer Genome Anatomy Project, NCI Gene Summary
TNFRSF6B COSMIC, Sanger Institute Somatic mutation information and related details
TNFRSF6B GEO Profiles, NCBI Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: TNFRSF6B (cancer-related)
Mohammadoo Khorasani M, Karami Tehrani F, Parizadeh SMR, Atri M Differential expression of alternative transcripts of soluble guanylyl cyclase, GYCY1a3 and GUCY1b3 genes, in the malignant and benign breast tumors. Nitric Oxide. 2019; 83:65-71 [PubMed] Related Publications
Extensive alterations in splicing is one of the molecular indicator for human cancers. Soluble guanylyl cyclase (sGC), an obligatory heterodimer, is composed of α1 and β1 subunits. Each subunit is encoded by a separate gene, GUCY1a3 and GUCY1b3, correspondingly. sGC activity has been regulated by an alternative splicing and it has an important effect on the breast cancer. sGC alternative splicing has been evaluated in the 55 malignant, 25 benign and 30 normal breast tissues using qRT-PCR and RT-PCR. The differences between groups were analyzed by Mann-Whitney U. The expression of six different splice forms have been detected, three for α1 and three for β1 sGC. Expressions of Tr1, Tr2 β1 sGC and Tr7, Tr6 α1 sGC mRNA in the malignant breast tumors were significantly lower than those of benign and normal breast tissues. However, the expression of Tr3 α1 sGC mRNA was significantly higher than that of benign and normal tissues. Present data have provided some evidences for an alteration in the expression of α1 and β1 sGC alternative splicing forms which may contribute to the loss of sGC functions in the breast cancer. The observed information might be discussed by the cGMP status.
Bou-Dargham MJ, Liu Y, Sang QA, Zhang J Subgrouping breast cancer patients based on immune evasion mechanisms unravels a high involvement of transforming growth factor-beta and decoy receptor 3. PLoS One. 2018; 13(12):e0207799 [PubMed] Free Access to Full ArticleRelated Publications
In the era of immunotherapy and personalized medicine, there is an urgent need for advancing the knowledge of immune evasion in different cancer types and identifying reliable biomarkers that guide both therapy selection and patient inclusion in clinical trials. Given the differential immune responses and evasion mechanisms in breast cancer, we expect to identify different breast cancer groups based on their expression of immune-related genes. For that, we used the sequential biclustering method on The Cancer Genome Atlas RNA-seq breast cancer data and identified 7 clusters. We found that 77.4% of the clustered tumor specimens evade through transforming growth factor-beta (TGF-β) immunosuppression, 57.7% through decoy receptor 3 (DcR3) counterattack, 48.0% through cytotoxic T-lymphocyte-associated protein 4 (CTLA4), and 34.3% through programmed cell death-1 (PD-1). TGF-β and DcR3 are potential novel drug targets for breast cancer immunotherapy. Targeting TGF-β and DcR3 may provide a powerful approach for treating breast cancer because 57.7% of patients overexpressed these two molecules. Furthermore, triple-negative breast cancer (TNBC) patients clustered equally into two subgroups: one with impaired antigen presentation and another with high leukocyte recruitment but four different evasion mechanisms. Thus, different TNBC patients may be treated with different immunotherapy approaches. We identified biomarkers to cluster patients into subgroups based on immune evasion mechanisms and guide the choice of immunotherapy. These findings provide a better understanding of patients' response to immunotherapies and shed light on the rational design of novel combination therapies.
Xie L, Chen Z, Liu H, et al. Effects of miR-340 on hepatocellular carcinoma by targeting the DcR3 gene. Dig Liver Dis. 2018; 50(3):291-296 [PubMed] Related Publications
In hepatocellular carcinoma (HCC), miR-340 plays a vital role in the regulation of tumor occurrence and deterioration, while DcR3 gene is involved in cancer cell proliferation and apoptosis. This study analyzed miR-340 in the serum of patients with HCC and healthy controls. Then, miR-340, DcR3, TGF-β1 and Smad2 expression were measured in HCC tissues and adjacent parts. Relationship between miR-340 and DcR3 was verified. Effects of miR-340 on human HepG2 cell proliferation and apoptosis were explored. miR-340, DcR3, TGF-β1, Smad2 mRNA and protein expression were also determined after miR-340 transfection. Compared with the control, miR-340 was significantly lower in the serum of the HCC patients (p < 0.01). miR-340 was lower in HCC tissues than in adjacent; however, DcR3, TGF-β1 and Smad2 were higher (p < 0.01). Furthermore, luciferase activity was significantly lower in the cells co-transfected with miR-340 mimics and DcR3-3'UTR-WT (p < 0.01), indicating that DcR3 was a target gene of miR-340. Moreover, decreased expression in DcR3, TGF-β1 and Smad2 was detected after miR-340 overexpression (p < 0.01), thus promoting apoptosis and blocking the proliferation of human HepG2 cells (p < 0.05). Furthermore, overexpression of DcR3 could activate the TGF-β1/Smad2 signal transduction pathway and increase the phosphorylation of Smad2. In conclusion, miR-340 plays a suppressive role in HCC development by targeting DcR3 and silencing the TGF-β1/Smad2 signaling pathway.
BACKGROUND: Decoy receptor 3 (DcR3) is a protein with anti-apoptotic effect that belongs to the tumor necrosis factor receptor superfamily. DcR3 is highly expressed in a variety of malignant tumors including cholangiocarcinoma and its expression was found to be related to the clinical stage, the invasion, and the metastasis of the tumor. This in vitro study aimed to investigate the effect of downregulated expression of DcR3 on cell viability, cell apoptosis, and cell cycle in cholangiocarcinoma cell line TFK-1. METHODS: Three different cell lines were cultured: human cholangiocarcinoma TFK-1, human biliary epithelial carcinoma HuCCT-1, and human cholangiocarcinoma RBE. The cholangiocarcinoma cell line with the highest expression of DcR3 was selected for further investigation. The expression of DcR3 was silenced/knocked down by transfection with DcR3-siRNA in the selected cell line. Various biological phenotype parameters such as cell viability, apoptosis, and cell cycle were observed. RESULTS: The mRNA and protein levels of DcR3 were measured in the three cell lines, and TFK-1 was selected. After the treatment with DcR3-siRNA for 48 h, DcR3 mRNA and protein expression in the treatment group were 38.45% (P < 0.01) and 48.03% (P < 0.05) of that of the control, respectively. It was found that the cell viability decreased to 61.87% of the control group (P < 0.01) after the downregulation of DcR3 in cholangiocarcinoma cell line TFK-1 by transfection with DcR3-siRNA, while the percentage of apoptotic cells was 2.98 times as compared with the control group (P < 0.05). Compared with the control group the ratio of G0/G1increased, and the ratio of G2/M decreased in the treatment group. However, the differences were not statistically significant. CONCLUSIONS: The effect of DcR3 on the growth and apoptosis of cholangiocarcinoma has been demonstrated. DcR3 is not only a predictive marker for malignant tumor but it is also likely to be a potential target for cancer gene therapy. Further studies should focus on exploring the binding ligand of DcR3, the signaling pathway involved, and the molecular mechanism for the regulation of DcR3 expression in cholangiocarcinoma.
Assessing the impact of genomic alterations on protein networks is fundamental in identifying the mechanisms that shape cancer heterogeneity. We have used isobaric labeling to characterize the proteomic landscapes of 50 colorectal cancer cell lines and to decipher the functional consequences of somatic genomic variants. The robust quantification of over 9,000 proteins and 11,000 phosphopeptides on average enabled the de novo construction of a functional protein correlation network, which ultimately exposed the collateral effects of mutations on protein complexes. CRISPR-cas9 deletion of key chromatin modifiers confirmed that the consequences of genomic alterations can propagate through protein interactions in a transcript-independent manner. Lastly, we leveraged the quantified proteome to perform unsupervised classification of the cell lines and to build predictive models of drug response in colorectal cancer. Overall, we provide a deep integrative view of the functional network and the molecular structure underlying the heterogeneity of colorectal cancer cells.
Decoy receptor 3 (DcR3), also known as tumor necrosis factor receptor (TNFR) superfamily member 6b (TNFRSF6B), is a soluble decoy receptor which can neutralize the biological functions of three members of tumor necrosis factor superfamily (TNFSF): Fas ligand (FasL), LIGHT, and TL1A. In addition to 'decoy' function, recombinant DcR3.Fc is able to modulate the activation and differentiation of dendritic cells (DCs) and macrophages via 'non-decoy' action. DcR3-treated DCs skew T cell differentiation into Th2 phenotype, while DcR3-treated macrophages behave M2 phenotype. DcR3 is upregulated in various cancer cells and several inflammatory tissues, and is regarded as a potential biomarker to predict inflammatory disease progression and cancer metastasis. However, whether DcR3 is a pathogenic factor or a suppressor to attenuate inflammatory reactions, has not been discussed comprehensively yet. Because mouse genome does not have DcR3, it is not feasible to investigate its physiological functions by gene-knockout approach. However, DcR3-mediated effects in vitro are determined via overexpressing DcR3 or addition of recombinant DcR3.Fc fusion protein. Moreover, CD68-driven DcR3 transgenic mice are used to investigate DcR3-mediated systemic effects in vivo. Upregulation of DcR3 during inflammatory reactions exerts negative-feedback to suppress inflammation, while tumor cells hijack DcR3 to prevent apoptosis and promote tumor growth and invasion. Thus, 'switch-on' of DcR3 expression may be feasible for the treatment of inflammatory diseases and enhance tissue repairing, while 'switch-off' of DcR3 expression can enhance tumor apoptosis and suppress tumor growth in vivo.
Protocadherin genes (PCDHs) have been suggested to act as tumor suppressor genes in various tumor types. Previous studies have demonstrated the upregulation of certain PCDH‑γ subfamily genes in nodal and duodenal follicular lymphoma (FL) using gene expression analyses. However, the mechanisms and associated molecular function of PCDH‑γ subfamily gene upregulation in FL remain to be elucidated. The present study examined the expression of PCDHGA3, an upregulated PCDH‑γ gene subfamily member, in B‑cell lymphoma 2 (BCL2)‑positive and ‑negative FL, and evaluated its association with tumor cell proliferation in an FL‑derived cell line. Immunohistochemical analysis demonstrated that the majority of FL grade 1‑2 samples (19/20; 95%) and over half of grade 3A FL samples (5/9; 56%) were PCDHGA3‑positive, whereas only 1/17 reactive lymphoid hyperplasia samples was positive. Notably, this positivity was widely observed in samples of BCL2‑negative FL (13/15; 87%) and FL with diffuse area (10/10; 100%). The FL‑derived cell line FL18 exhibited strong PCDHGA3 expression, similar to the patient samples, and its proliferation was suppressed by PCDHGA3 gene knockdown. Genes expressed concomitantly with PCDHGA3 were selected from gene expression data, and TNFRSF6B, a member of the tumor necrosis factor receptor superfamily, was among the top five most strongly correlated genes. Coexpression of TNFRSF6B and PCDHGA3 was observed immunohistochemically in FL18 cells, suggesting potential cooperation in tumor cell maintenance. In conclusion, the results of the present study indicated that PCDHGA3 was expressed in FL irrespective of BCL2 status and grading and was associated with cell proliferation. Further studies involving molecular genetic analyses are required to elucidate the mechanisms underlying the activity of PCDHGA3 in FL.
Decoy receptor 3 (DcR3), a novel member of the tumor necrosis factor receptor (TNFR) family, was recently reported to be associated with tumorigenesis and metastasis. However, the role of DcR3 in human colorectal cancer (CRC) has not been fully elucidated. In this study, we found that DcR3 expression was significantly higher in human colorectal cancer tissues than in paired normal tissues, and that DcR3 expression was strongly correlated with tumor invasion, lymph node metastases and poor prognoses. Moreover, DcR3 overexpression significantly enhanced CRC cell proliferation and migration in vitro and tumorigenesis in vivo. Conversely, DcR3 knockdown significantly repressed CRC cell proliferation and migration in vitro, and DcR3 deficiency also attenuated CRC tumorigenesis and metastasis in vivo. Functionally, DcR3 was essential for TGF-β3/SMAD-mediated epithelial-mesenchymal transition (EMT) of CRC cells. Importantly, cooperation between DcR3 and TGF-β3/SMAD-EMT signaling-related protein expression was correlated with survival and survival time in CRC patients. In conclusion, our results demonstrate that DcR3 may be a prognostic biomarker for CRC and that this receptor facilitates CRC development and metastasis by participating in TGF-β3/SMAD-mediated EMT of CRC cells.
Decoy Receptor 3 (DcR3), also called TNFRSF6β, is a member of the tumor necrosis factor receptor superfamily and is a soluble receptor for FasL. DcR3 is overexpressed in cancers and contributes to tumorigenesis through immune suppression and promotion of angiogenesis. We found that DcR3 is overexpressed in breast infiltrating ductal carcinoma (IDC) cells as compared with normal controls. We also conducted a case-control study analyzing associations of DcR3 polymorphisms with breast IDC risk. Subjects included 531 females with breast IDC and 592 age-matched healthy controls. Four DcR3 single nucleotide polymorphism loci with minor frequencies of more than 5% (rs3208008, rs41309931, rs2297441 and rs1291207) were genotyped using polymerase chain reaction restriction fragment length polymorphism and sequencing. Our results revealed significant differences in rs41309931genotypes and alleles (P < 0.01). Based on Haploview software analysis, the haplotype block Ars3208008 Grs41309931 Grs2297441 Ars1291207 exhibited the highest frequency, but, haplotype blocks Ars3208008 Trs41309931 Grs2297441 Ars1291207 and Crs3208008 Grs41309931 Grs2297441 Ars1291207 were associated with breast IDC risk. This study also detected associations between DcR3 gene polymorphisms and the clinicopathological features of breast IDC, including lymph node metastasis and C-erbB2, P53, estrogen receptor and progesterone receptor status. These data indicate that DcR3 gene polymorphisms are associated with sporadic breast IDC risk in Northeast Chinese females.
Lin JD, Fu SS, Chen JY, et al. Clinical Manifestations and Gene Expression in Patients with Conventional Papillary Thyroid Carcinoma Carrying the BRAF(V600E) Mutation and BRAF Pseudogene. Thyroid. 2016; 26(5):691-704 [PubMed] Related Publications
BACKGROUND: The association of BRAF(V600E) with the clinical manifestations of papillary thyroid carcinoma (PTC) remains controversial. Recent studies have shown that the BRAF pseudogene can activate the MAPK pathway and induce tumorigenesis. This study investigated the association of BRAF(V600E), the BRAF pseudogene, and their mRNA levels with clinical features and thyroid-specific gene expression in conventional PTCs. MATERIALS AND METHODS: A total of 78 specimens were collected from patients with conventional PTCs. RNA was isolated, and quantitative polymerase chain reaction was used to measure the mRNA levels of BRAF, the BRAF pseudogene, and thyroid-specific and tumor-related genes. Immunohistochemical (IHC) staining of BRAF, ERK, sodium-iodide symporter (NIS), thyrotropin receptor, glucose transporter 1, and Ki67 was also performed. RESULTS: BRAF(V600E) and the BRAF pseudogene were detected in 73.0% (57/78) and 91.7% (44/48), respectively, of the conventional PTCs. The presence of BRAF(V600E) was not associated with the multiple clinical features assessed or the recurrence rate during 76.9 ± 47.2 months of follow-up. Neither was it associated with IHC staining or tumor-related/thyroid-specific gene expression, except for decreased NIS gene expression. The BRAF pseudogene was not associated with clinical characteristics or thyroid-specific gene expression, except for decreased decoy receptor 3 (DCR3) expression. High BRAF mRNA levels were associated with bilateral and multifocal lesions, and BRAF-pseudogene mRNA levels were positively correlated with BRAF mRNA levels (r = 0.415, p = 0.009). CONCLUSION: These results do not support the use of the BRAF(V600E) mutation as a prognostic marker of conventional PTC. However, the association of high BRAF mRNA levels with more advanced clinical features suggests that BRAF mRNA levels might be a more useful clinical marker of PTCs, independent of the BRAF(V600E) mutation status. The correlation between BRAF-pseudogene mRNA levels and BRAF mRNA levels in PTCs is in agreement with the hypothesis that the BRAF pseudogene regulates BRAF expression during tumorigenesis by acting as competitive noncoding RNA. However, additional studies with larger sample sizes are required to confirm these findings.
Zhang Y, Li D, Zhao X, et al. Decoy receptor 3 suppresses FasL-induced apoptosis via ERK1/2 activation in pancreatic cancer cells. Biochem Biophys Res Commun. 2015; 463(4):1144-51 [PubMed] Related Publications
Resistance to Fas Ligand (FasL) mediated apoptosis plays an important role in tumorigenesis. Decoy receptor 3 (DcR3) is reported to interact with FasL and is overexpressed in some malignant tumors. We sought to investigate the role of DcR3 in resistance to FasL in pancreatic cancer. We compared expression of apoptosis related genes between FasL-resistant SW1990 and FasL-sensitive Patu8988 pancreatic cell lines by microarray analysis. We explored the impact of siRNA knockdown of, or exogenous supplementation with, DcR3 on FasL-induced cell growth inhibition in pancreatic cancer cell lines and expression of proteins involved in apoptotic signaling. We assessed the level of DcR3 protein and ERK1/2 phosphorylation in tumor and non-tumor tissue samples of 66 patients with pancreatic carcinoma. RNAi knockdown of DcR3 expression in SW1990 cells reduced resistance to FasL-induced apoptosis, and supplementation of Patu8988 with rDcR3 had the opposite effect. RNAi knockdown of DcR3 in SW1990 cells elevated expression of caspase 3, 8 and 9, and reduced ERK1/2 phosphorylation (P < 0.05), but did not alter phosphorylated-Akt expression. 47 tumor tissue specimens, but only 15 matched non-tumor specimens stained for DcR3 (χ(2) = 31.1447, P < 0.001). The proliferation index of DcR3 positive specimens (14.26 ± 2.67%) was significantly higher than that of DcR3 negative specimens (43.58 ± 7.88%, P < 0.01). DcR3 expression positively correlated with p-ERK1/2 expression in pancreatic cancer tissues (r = 0.607, P < 0.001). DcR3 enhances ERK1/2 phosphorylation and opposes FasL signaling in pancreatic cancer cells.
UNLABELLED: Using high-throughput RNA sequencing data from 50 common lymphoma cell culture models from the Cancer Cell Line Encyclopedia project, we performed an unbiased global interrogation for the presence of a panel of 740 viruses and strains known to infect human and other mammalian cells. This led to the findings of previously identified infections by Epstein-Barr virus (EBV), Kaposi's sarcoma herpesvirus (KSHV), and human T-lymphotropic virus type 1 (HTLV-1). In addition, we also found a previously unreported infection of one cell line (DEL) with a murine leukemia virus. High expression of murine leukemia virus (MuLV) transcripts was observed in DEL cells, and we identified four transcriptionally active integration sites, one being in the TNFRSF6B gene. We also found low levels of MuLV reads in a number of other cell lines and provided evidence suggesting cross-contamination during sequencing. Analysis of HTLV-1 integrations in two cell lines, HuT 102 and MJ, identified 14 and 66 transcriptionally active integration sites with potentially activating integrations in immune regulatory genes, including interleukin-15 (IL-15), IL-6ST, STAT5B, HIVEP1, and IL-9R. Although KSHV and EBV do not typically integrate into the genome, we investigated a previously identified integration of EBV into the BACH2 locus in Raji cells. This analysis identified a BACH2 disruption mechanism involving splice donor sequestration. Through viral gene expression analysis, we detected expression of stable intronic RNAs from the EBV BamHI W repeats that may be part of long transcripts spanning the repeat region. We also observed transcripts at the EBV vIL-10 locus exclusively in the Hodgkin's lymphoma cell line, Hs 611.T, the expression of which were uncoupled from other lytic genes. Assessment of the KSHV viral transcriptome in BCP-1 cells showed expression of the viral immune regulators, K2/vIL-6, K4/vIL-8-like vCCL1, and K5/E2-ubiquitin ligase 1 that was significantly higher than expression of the latency-associated nuclear antigen. Together, this investigation sheds light into the virus composition across these lymphoma model systems and provides insights into common viral mechanistic principles. IMPORTANCE: Viruses cause cancer in humans. In lymphomas the Epstein-Barr virus (EBV), Kaposi's sarcoma herpesvirus (KSHV) and human T-lymphotropic virus type 1 are major contributors to oncogenesis. We assessed virus-host interactions using a high throughput sequencing method that facilitates the discovery of new virus-host associations and the investigation into how the viruses alter their host environment. We found a previously unknown murine leukemia virus infection in one cell line. We identified cellular genes, including cytokine regulators, that are disrupted by virus integration, and we determined mechanisms through which virus integration causes deregulation of cellular gene expression. Investigation into the KSHV transcriptome in the BCP-1 cell line revealed high-level expression of immune signaling genes. EBV transcriptome analysis showed expression of vIL-10 transcripts in a Hodgkin's lymphoma that was uncoupled from lytic genes. These findings illustrate unique mechanisms of viral gene regulation and to the importance of virus-mediated host immune signaling in lymphomas.
Ovarian cancer linked to Lynch syndrome represents a rare subset that typically presents at young age as early-stage tumors with an overrepresentation of endometrioid and clear cell histologies. We investigated the molecular profiles of Lynch syndrome-associated and sporadic ovarian cancer with the aim to identify key discriminators and central tumorigenic mechanisms in hereditary ovarian cancer. Global gene expression profiling using whole-genome c-DNA-mediated Annealing, Selection, extension, and Ligation was applied to 48 histopathologically matched Lynch syndrome-associated and sporadic ovarian cancers. Lynch syndrome-associated and sporadic ovarian cancers differed by 349 significantly deregulated genes, including PTPRH, BIRC3, SHH and TNFRSF6B. The genes involved were predominantly linked to cell growth, proliferation, and cell-to-cell signaling and interaction. When stratified for histologic subtype, hierarchical clustering confirmed distinct differences related to heredity in the endometrioid and serous subtypes. Furthermore, separate clustering was achieved in an independent, publically available data set. The distinct genetic signatures in Lynch syndrome-associated and sporadic ovarian cancers point to alternative preferred tumorigenic routes and suggest that genetic discriminators may be relevant for molecular diagnostics and targeted therapeutics.
Zheng XF, Miao LY, Li S, Wang YB Promotive Effects of Dcr3 Gene on the Occurrence and Progression of Gastric Cancer and its Mechanism. Hepatogastroenterology. 2014; 61(131):880-4 [PubMed] Related Publications
BACKGROUND/AIMS: To observe the effects of DcR3 gene on the occurrence and progression of gastric cancer and explore its mechanism. METHODOLOGY: DcR3 mRNA expressions in both gastric normal tissue and gastric cancer tissue were detected with RT-PCR. Apoptosis index (AI) was determined with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). RESULTS: Positive rate of DcR3 mRNA expression was significantly higher in gastric cancer tissue than in gastric normal tissue (P < 0.01). The level of DcR3 mRNA expression was related to differentiation, lymphatic metastasis and TNM staging (P < 0.05). The level of DcR3 mRNA expression was inversely correlated with AI (P < 0.01). CONCLUSION: DcR3 plays an important role in the occurrence and progression of gastric cancer possibly through inhibiting gastric cancer cell apoptosis.
BACKGROUND: Overexpression of decoy receptor 3 (DcR3) have been reported in various classes of malignancies. However, its expression and clinicopathological contribution in gliomas has not been fully elucidated. OBJECTIVE: To explore the expression and clinical significance of DcR3 protein in relation to tumor cell differentiation and proliferation in glioma cell lines and tissues. METHODS: One hundred and twenty-five samples of glioma patients and 18 cases of normal brain tissues were recruited. The expression of DcR3 protein was detected using immunohistochemistry. Tumor differentiation was assessed by histologic characters and the status of glial fibrillary acidic protein (GFAP). Tumor cell labeling indexes (LIs) of Ki-67 and PCNA were also obtained. The relationship between the DcR3 level and clinicopathological features was investigated, including tumor differentiation, LIs, and survival. Meanwhile, the expression of DcR3 protein was also measured in the supernatants of 8 glioma cell lines and glioma cells freshly prepared from 8 human glioblastoma specimens by using western blot. RESULTS: The level of DcR3 protein in gliomas was significantly higher than that in normal brain tissues (P < 0.01). DcR3 expression showed positive correlations with tumor pathological grade (r = 0.621, P < 0.01) and negative with GFAP expression (r = -0.489, P < 0.01). Furthermore, there were positive correlations between DcR3 expression and Ki-67, PCNA LIs (r = 0.529, P < 0.01; r = 0.556, P < 0.01). The survival in the DcR3 negative group was 50 ± 1.79 months, longer than that of the DcR3 positive group (48.36 ± 2.90), however, without significance (P = 0.149). Different levels of DcR3 could also be detected in the culturing supernatants of all the 8 glioma cell lines and glioma cells freshly obtained from 8 human glioblastoma specimens. CONCLUSIONS: The overexpression of DcR3 might play a crucial role in the tumorigenesis, differentiation, and proliferation of glioma.
Most human pancreatic cancer cells are resistant to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. However, the mechanisms by which pancreatic cancer cells utilize their extracellular molecules to counteract the proapoptotic signaling mediated by the TNF family are largely unknown. In this study, we demonstrate for the first time that DcR3, a secreted decoy receptor that malignant pancreatic cancer cells express at a high level, acts as an extracellular antiapoptotic molecule by binding to TRAIL and counteracting its death-promoting function. The reduction of DcR3 with siRNA unmasked TRAIL and greatly enhanced TRAIL-induced apoptosis. Gemcitabine, a first-line drug for pancreatic cancer, also reduced the level of DcR3. The addition of DcR3 siRNA further enhanced gemcitabine-induced apoptosis. Notably, our in vivo study demonstrated that the therapeutic effect of gemcitabine could be enhanced via further reduction of DcR3, suggesting that downregulation of DcR3 in tumor cells could tip the balance of pancreatic cells towards apoptosis and potentially serve as a new strategy for pancreatic cancer therapy.
Weissinger D, Tagscherer KE, Macher-Göppinger S, et al. The soluble Decoy Receptor 3 is regulated by a PI3K-dependent mechanism and promotes migration and invasion in renal cell carcinoma. Mol Cancer. 2013; 12(1):120 [PubMed] Free Access to Full ArticleRelated Publications
BACKGROUND: Overexpression of Decoy Receptor 3 (DcR3), a soluble member of the tumor necrosis factor receptor superfamily, is a common event in several types of cancer. In renal cell carcinoma (RCC), DcR3 overexpression is associated with lymph node and distant metastasis as well as a poor prognosis. However, the functional role and regulation of DcR3 expression in RCC is so far unknown. METHODS: Modulation of DcR3 expression by siRNA and ectopic gene expression, respectively, was performed in ACHN and 769-P RCC cell lines. Functional effects of a modulated DcR3 expression were analyzed with regard to migration, invasion, adhesion, clonogenicity, and proliferation. Furthermore, quantitative RT-PCR and immunoblot analyses were performed to evaluate the expression of downstream mediators of DcR3. In further experiments, luciferase assays, quantitative RT-PCR and immunoblot analyses were applied to study the regulation of DcR3 expression in RCC. Additionally, an ex vivo tissue slice culture technique combined with immunohistochemistry was used to study the regulation of DcR3 expression in human RCC specimens. RESULTS: Here, we show that DcR3 promotes adhesion, migration and invasiveness of RCC cells. The DcR3-dependent increase in cellular invasiveness is accompanied with an up-regulation of integrin alpha 4, matrixmetalloproteinase 7 and urokinase plasminogen activator (uPA). Further, we identified a signaling pathway regulating DcR3 expression in RCC. Using in vitro experiments as well as an ex vivo RCC tissue slice culture model, we demonstrate that expression of DcR3 is regulated in a PI3K/AKT-dependent manner involving the transcription factor nuclear factor of activated T-cells (NFAT). CONCLUSIONS: Taken together, our results identify DcR3 as a key driver of tumor cell dissemination and suggest DcR3 as a promising target for rational therapy of RCC.
Yu W, Xu YC, Tao Y, et al. DcR3 regulates the growth and metastatic potential of SW480 colon cancer cells. Oncol Rep. 2013; 30(6):2741-8 [PubMed] Related Publications
Decoy receptor 3 (DcR3) is considered to have anti‑apoptotic and pro-metastatic functions, suggesting it might be a therapeutic target. We examined the role and mechanisms of DcR3 on growth and the metastatic ability of SW480 colon cancer cells to provide therapeutic information for targeting DcR3 by RNA interference (RNAi) technology. Growth and the metastatic ability were inhibited, apoptosis was induced and cell cycle profile was changed after decreasing DcR3 expression, with lower levels of vascular endothelial growth factors (VEGFs) and matrix metalloproteinases (MMPs) expression. Our results implied the therapeutic potential of silencing DcR3 expression by RNAi in colon cancer.
Zhou J, Song S, He S, et al. Silencing of decoy receptor 3 (DcR3) expression by siRNA in pancreatic carcinoma cells induces Fas ligand-mediated apoptosis in vitro and in vivo. Int J Mol Med. 2013; 32(3):653-60 [PubMed] Related Publications
Decoy receptor 3 (DcR3) is abundantly expressed in human tumors and protects cells from a wide range of apoptotic stimuli. In this study, we demonstrate that DcR3 is overexpressed in pancreatic carcinoma cells, and that the pancreatic carcinoma cell lines, Panc-1 and SW1990, are resistant to Fas ligand (FasL)-mediated apoptosis. To further define the function of DcR3 in cell growth and apoptosis, we used small interfering RNA (siRNA) to knockdown the expression of the DcR3 gene in Panc-1 and SW1990 cells. Our results revealed that the silencing of DcR3 expression enhanced the inhibitory effects of FasL and reduced the capabiltiy of the cells for proliferation and colony formation in vitro. In addition, the downregulation of DcR3 modulated the cell apoptotic regulators, Fas-associated death domain (FADD), caspase‑3 and caspase‑8, thus triggering cell apoptosis. Furthermore, the knockdown of DcR3 inhibited the growth of Panc-1 tumor xenografts. Taken together, our findings indicate that DcR3 is important in cancer progression and may be a used as a potential therapeutic target for the gene therapy of pancreatic carcinoma.
Decoy receptor 3 (DcR3) is a soluble secreted protein that belongs to the tumor necrosis factor receptor (TNFR) superfamily. DcR3 inhibits the Fas ligand (FasL)/Fas apoptotic pathway by binding to FasL, competitively with Fas receptor. Previous studies have reported that overexpression of DcR3 has been detected in various human malignancies and that DcR3 functions as a 'decoy' for FasL to inhibit FasL-induced apoptosis. In addition, recent studies have revealed that DcR3 has 'non-decoy' functions to promote tumor cell migration and invasion, suggesting that DcR3 may play important roles in tumor progression by decoy and non-decoy functions. We have previously reported that overexpression of DcR3 was observed in human malignant fibrous histiocytoma (MFH), however, the roles of DcR3 in MFH have not been studied. In the present study, to elucidate the roles of DcR3 in tumor progression of MFH, we examined the effects of DcR3 inhibition on cell apoptosis, migration and invasion in human MFH cells. siRNA knockdown of DcR3 enhanced the FasL-induced apoptotic activity and significantly decreased cell migration and invasion with a decrease in the activation of phosphatidylinositol 3 kinase (PI3K)/Akt and matrix metalloproteinase (MMP)-2. The findings in this study strongly suggest that DcR3 plays important roles in tumor progression of human MFH by decoy as well as non-decoy functions and that DcR3 may serve as a potent therapeutic target for human MFH.
BACKGROUND: Decoy receptor 3 (DcR3), a member of the tumor necrosis factor receptor (TNFR) superfamily, is associated with anti-tumor immunity suppression. It is highly expressed in many tumors, and its expression can be regulated by the MAPK/MEK/ERK signaling pathway. The MAPK/MEK/ERK pathway has been reported to be a regulator in tumor occurrence, development and clonal expansion. External-signal regulated kinase (ERK) is a vital member of this pathway. RESULTS: The expression of DcR3 and ERK1/2 in tumor tissues of gastric cancer patients was significantly higher than the non-cancerous group (P < 0.05). There was no statistical difference among tumor tissues from patients with different ages or gender, and even of different differentiation (P > 0.05). However, in patients with stage I gastric cancer, the DcR3 and ERK1/2 levels were significantly lower than patients with more advanced stages. CONCLUSIONS: DcR3 and ERK1/2 play a vital role in the development of gastric cancer, and they may be new markers for indicating the efficiency of gastric cancer treatment in the future.
Connor JP, Felder M, Kapur A, Onujiogu N DcR3 binds to ovarian cancer via heparan sulfate proteoglycans and modulates tumor cells response to platinum with corresponding alteration in the expression of BRCA1. BMC Cancer. 2012; 12:176 [PubMed] Free Access to Full ArticleRelated Publications
BACKGROUND: Overcoming platinum resistance is a major obstacle in the treatment of Epithelial Ovarian Cancer (EOC). In our previous work Decoy Receptor 3 (DcR3) was found to be related to platinum resistance. The major objective of this work was to define the cellular interaction of DcR3 with EOC and to explore its effects on platinum responsiveness. METHODS: We studied cell lines and primary cultures for the expression of and the cells ability to bind DcR3. Cells were cultured with DcR3 and then exposed to platinum. Cell viability was determined by MTT assay. Finally, the cells molecular response to DcR3 was studied using real time RT-PCR based differential expression arrays, standard RT-PCR, and Western blot. RESULTS: High DcR3 in the peritoneal cavity of women with EOC is associated with significantly shorter time to first recurrence after platinum based therapy (p = 0.02). None-malignant cells contribute DcR3 in the peritoneal cavity. The cell lines studied do not secrete DcR3; however they all bind exogenous DcR3 to their surface implying that they can be effected by DcR3 from other sources. DcR3s protein binding partners are minimally expressed or negative, however, all cells expressed the DcR3 binding Heparan Sulfate Proteoglycans (HSPGs) Syndecans-2, and CD44v3. DcR3 binding was inhibited by heparin and heparinase. After DcR3 exposure both SKOV-3 and OVCAR-3 became more resistant to platinum with 15% more cells surviving at high doses. On the contrary CaOV3 became more sensitive to platinum with 20-25% more cell death. PCR array analysis showed increase expression of BRCA1 mRNA in SKOV-3 and OVCAR-3 and decreased BRCA1 expression in CaOV-3 after exposure to DcR3. This was confirmed by gene specific real time PCR and Western blot analysis. CONCLUSIONS: Non-malignant cells contribute to the high levels of DcR3 in ovarian cancer. DcR3 binds readily to EOC cells via HSPGs and alter their responsiveness to platinum chemotherapy. The paradoxical responses seen were related to the expression pattern of HSPGs available on the cells surface to interact with. Although the mechanism behind this is not completely known alterations in DNA repair pathways including the expression of BRCA1 appear to be involved.
Zhou J, Song SD, Li DC, et al. Clinical significance of expression and amplification of the DcR3 gene in pancreatic carcinomas. Asian Pac J Cancer Prev. 2012; 13(2):719-24 [PubMed] Related Publications
This study aimed to investigate the clinical significance of expression and amplification of decoy receptor 3 (DcR3) in pancreatic carcinomas (PC). mRNA expression was detected by PQ-PCR, and amplification was determined. DcR3 protein expression was detected by immunohistochemistry and ELISA. Correlations between DcR3 expression and clinical pathological factors were analyzed. The relative amount of DcR3 in PC tissues and non-cancerous tissues showed a statistically significant difference, 21 cases displaying more than two fold DcR3 amplification, while no such amplification was found in normal pancreatic tissues. DcR3 positive cell staining was located in the cytoplasm. The positive rate of DcR3 in PC and non-cancerous tissues showed a significant difference. DcR3 mRNA expression was correlated with clinical staging, size of the tumor, lymph node metastasis and histological staging, while protein expression was correlated with clinical data like tumor size. DcR3 gene amplification only correlated with tumor size. The level of DcR3 in serum of the PC resectable group before operation was 72.2±10.2 pg/ml, showing a significant difference compared to gallbladder carcinoma group (GC) or pancreatic benign tumor (PBT) group (P <0.01). In conclusion, DcR3 amplification is correlated with DcR3 expression in PC tissues, especially those clinical pathological factors which reflect tumor progression. Assessment of DcR3 level in sera of PC patients may be helpful for the early diagnosis and prognostic judgement.
Ge Z, Sanders AJ, Ye L, et al. Expression of death decoy receptor-3 (DcR3) in human breast cancer and its functional effects on breast cancer cells in vitro. J Exp Ther Oncol. 2011; 9(2):109-18 [PubMed] Related Publications
BACKGROUND: Death Decoy Receptor-3 (DcR3), otherwise known as tumour necrosis factor receptor superfamily member 6b, is suggested to be involved in the progression and immune evasion of malignant tumours. Its ligands include FASL and LIGHT (Tumour necrosis factor ligand superfamily member 14). DcR3 has been found to be amplified in certain solid tumours. However, its role in breast tumours remains unclear. In the present study, we examined the role played by DcR3 in MCF7 and MDA-MB-231 cell lines. MATERIALS AND METHODS: The expression of DcR3 was examined in MCF7 and MDA-MB-231 cell lines using immunocytochemical staining and RT-PCR. Anti-DcR3 hammerhead ribozyme transgenes were constructed and transfected into cells to create DcR3 knock-down cell sublines. The biological impact of modifying DcR3 expression in breast cancer cells was evaluated using a variety of in vitro assays, including growth, adhesion, migration and invasion models. RESULTS: MCF7 and MDA-MB-231 cells, usually expressing DcR3, were transfected with the anti-DcR3 ribozyme transgene. Stable transfectants containing the DcR3 ribozyme transgene (MCF7DcR3KO, MDA-MB-231DcR3KO) displayed a reduction of DcR3 expression at mRNA and protein levels. DcR3 knockdown in MCF7 cells was found to significantly reduce invasive capacity compared to pEF6 control cell lines (30.78 +/- 6.40 vs.151.67 +/- 17.67 P < 0.001). The rate of migration in MCF7DcR3KO was significantly lower than MCF7pEF6 (P < 0.001). In contrast, no such significant differences was seen between MDA-MB-231DcR3KO and MDA-MB-231pEF6. CONCLUSION: Suppressing DcR3 expression was found to have an inhibitory effect on cellular invasion and migration in MCF7 breast cancer cells. This suggests that the invasion and migration capacity of this breast cancer cell line may, at least partly, depend on DcR3. DcR3 may be regarded as a negative regulator for aggressiveness during the development and progression of certain types of breast cancer.
Yoo S, Jang J, Kim S, et al. Expression of DcR3 and its effects in kaposi's sarcoma-associated herpesvirus-infected human endothelial cells. Intervirology. 2012; 55(1):45-52 [PubMed] Related Publications
OBJECTIVE: Kaposi's sarcoma-associated herpesvirus (KSHV) is classified as a gamma-herpesvirus and it causes Kaposi's sarcoma in patients infected with the human immunodeficiency virus (HIV). Decoy receptor 3 (DcR3) is known as a decoy receptor for Fas ligand, LIGHT and TL1A and it can neutralize the biological effect of TL1A by inhibiting the TL1A-DR3 interaction in human endothelial cells. The present study examined the expression of DcR3 in human endothelial cells and its effect during the early stages of KSHV infection. METHODS: The expression of DcR3 was assessed using real-time RT-PCR and ELISA in human umbilical cord vein endothelial cells (HUVECs) infected with KSHV. Cell proliferation and apoptosis of KSHV-infected HUVECs were assessed after treatment of infected cells with an anti-DcR3 antibody or recombinant human TL1A. RESULTS: DcR3 expression was induced during the early phase of KSHV infection. Inhibition of DcR3 with anti-DcR3 antibodies or recombinant human TL1A-induced apoptosis in KSHV-infected HUVECs. CONCLUSION: The expression of DcR3 plays an important role in the prevention of apoptosis in HUVECs during the early phases of KSHV infection, thus ensuring the successful establishment and maintenance of the viral infection.
OBJECTIVE: Decoy receptor 3 (DcR3), a member of the tumor necrosis factor receptor superfamily, is amplified and over-expressed in various cancers. The objective of the present study was to investigate the concentration of DcR3 in sera of hepatocellular carcinoma (HCC) patients and its clinical significance. METHODS: Serum concentrations of DcR3 were measured by enzyme-linked immunosorbent assay (ELISA) in 67 patients with HCC, 8 with liver cirrhosis, 17 with cholecystitis, and in 28 healthy individuals. Immunohistochemistry was employed to access protein expression of DcR3 in the corresponding HCC tissues. RESULTS: Serum concentrations of DcR3 in patients with HCC or cirrhosis were significantly higher than in healthy individuals (P < 0.01). Moreover, serum concentrations of DcR3 in HCC patients were associated with TNM stage, para-cirrhosis, capsular infiltration, and metastasis or recurrence of disease (P < 0.05). There was a positive correlation between the serum concentration of DcR3 and protein expression in HCC tissues (r = 0.472, P < 0.01). CONCLUSIONS: The high serum concentration of DcR3 might play a certain role in pathogenesis, progress, and metastasis of HCC. Moreover, DcR3 might serve as a valuable molecular indicator in early diagnosis and contribute to predicting the clinical outcome in HCC patients.
Sung HY, Wu HG, Ahn JH, Park WY Dcr3 inhibit p53-dependent apoptosis in gamma-irradiated lung cancer cells. Int J Radiat Biol. 2010; 86(9):780-90 [PubMed] Related Publications
PURPOSE: To identify genes responsible for the radiosensitivity, we investigated the role of the differential gene expression profiles by comparing radioresistant H1299 with radiosensitive H460 lung cancer cell lines. MATERIALS AND METHODS: mRNA profiles of lung cancer cell lines were assessed using microarray, and subsequent validation was performed with qRT-PCR (Quantitative real time-polymerase chain reaction). The expression levels of differentially expressed genes were determined by Western blot and the radioresistance of lung cancer cell lines was measured by clonogenic assay. RESULTS: From the differentially expressed apoptosis-related genes between H1299 and H460, we found Dcr3 (Decoy receptor 3, also known as TNFRSF6B; Tumour necrosis factor receptor super family member 6B) expression was significantly (P = 4.38 x 10(-7)) higher in H1299 cells than H460 cells. Moreover, the Dcr3 mRNA expression level in the radioresistant cell lines (H1299, A549, DLD1, MB231, MB157) was increased in comparison to the radiosensitive cell lines (ME180, Caski, U87MG, MCF7, H460). Overexpression of Dcr3 increased the survival rate of radiosensitive H460, MCF7, and U87MG cells, and knockdown of Dcr3 abolished the radioresistance of A549 cells. The survival rate of p53 (Tumour protein 53)-deficient H1299 after gamma-irradiation was not affected by the suppression of Dcr3 expression. However, when we introduced p53 into H1299 cells, siDcr3 (siRNA of Dcr3) suppressed the radioresistance of H1299 cells by inducing p53-dependent Fas (Fas receptor, also known as TNFRSF6; Tumour necrosis factor receptor super family member 6)-mediated apoptosis pathway. CONCLUSION: Characterisation of gene expression profiles in two lung cancer cell lines revealed that Dcr3 expression and p53-dependent apoptosis signalling pathway regulate cellular response to ionising radiation.
Xiong G, Guo H, Wang K, et al. Polymorphisms of decoy receptor 3 are associated with risk of esophageal squamous cell carcinoma in Chinese Han. Tumour Biol. 2010; 31(5):443-9 [PubMed] Related Publications
Decoy receptor 3 (DcR3) is a soluble receptor without transmembrane and intracellular sequences in its peptide. It can bind to and inactivate the apoptosis-inducing ligand FasL, LIGHT, and TL1A. The aims of this study are to genotype the two polymorphisms in the promotor of DcR3 in esophageal squamous cell cancer patients and controls and analyze the association between individual genetic variation and susceptibility to esophageal squamous cell carcinoma (ESCC). A total of 444 Chinese ESCC patients and 468 matched cancer-free controls were evaluated for the two single nucleotide polymorphisms (SNPs) in DCR3. Polymorphisms were genotyped using the SNPShot technique. The expression of DCR3 in cancer tissues was detected by reverse transcription-polymerase chain reaction. There were significant differences in the allele's distribution of the two SNPs among ESCC cases and controls (P < 0.01). Compared with the 147TT genotype, the 147CC genotype was associated with significant elevated risk of ESCC (odds ratio, 1.89; 95% confidence interval, 1.30-2.96). The risk of 147CC genotype was more notable (odds ratio, 2.19; 95% confidence interval, 1.32-3.64) in the smokers than in the nonsmokers (odds ratio, 1.25; 95% confidence interval, 0.59-2.69). In the stratification analyses, we also found there was a strong correlation between 147 CC and the clinical TNM stage (P < 0.01). Furthermore, significant difference in DCR3 expression in ESCC tissues was found between subgroups with different 147C/T variant. Our finding suggested that DcR3 promoter polymorphism 147C/T might influence the susceptibility to ESCC in the Chinese Han population, maybe by influencing DcR3 expression.
DNA copy-number gains of chromosomes 8q, 13q, and 20q are frequently observed in gastric cancers. Moreover gain of chromosome 20q has been associated with lymph node metastasis. The aim of this study was to correlate DNA copy-number changes of individual genes on chromosomes 8q, 13q, and 20q in gastric adenocarcinomas to clinicopathological data. DNA isolated from 63 formalin-fixed and paraffin-embedded gastric adenocarcinoma tissue samples was analyzed by whole-genome microarray comparative genomic hybridization and by multiplex ligation-dependent probe amplification (MLPA), targeting 58 individual genes on chromosomes 8, 13, and 20. Using array comparative genomic hybridization, gains on 8q, 13q, and 20q were observed in 49 (77.8%), 25 (39.7%), and 49 (77.8%) gastric adenocarcinomas, respectively. Gain of chromosome 20q was significantly correlated with lymph node metastases (p = 0.05) and histological type (p = 0.02). MLPA revealed several genes to be frequently gained in DNA copy number. The oncogene c-myc on 8q was gained in 73% of the cancers, while FOXO1A and ATP7B on 13q were both gained in 28.6% of the cases. Multiple genes on chromosome 20q showed gains in more than 60% of the cancers. DNA copy-number gains of TNFRSF6B (20q13.3) and ZNF217 (20q13.2) were significantly associated with lymph node metastasis (p = 0.02) and histological type (p = 0.02), respectively. In summary, gains of chromosomes 8q, 13q, and 20q in gastric adenocarcinomas harbor DNA copy-number gains of known and putative oncogenes. ZNF217 and TNFRSF6B are associated with important clinicopathological variables, including lymph node status.
Chen G, Luo D Expression of decoy receptor 3 in liver tissue microarrays. Natl Med J India. 2008 Nov-Dec; 21(6):275-8 [PubMed] Related Publications
BACKGROUND: Decoy receptor 3 (DcR3), a new member of the tumour necrosis factor receptor (TNFR) superfamily, is amplified and overexpressed in various cancers. We investigated the expression of DcR3 protein in liver tissue microarrays and assessed its importance in patients with hepatocellular carcinoma (HCC). METHODS: In this retrospective study, tissue from 120 patients with HCC, 48 with tissue at least 2 cm away from the tumour (juxta-tumour tissue), 62 with cirrhosis and 23 with normal livers were studied as tissue microarrays. Immunohistochemistry was used to detect the expression of DcR3. Statistical analyses were done to assess the association between DcR3 expression and the clinicopathological features of HCC. RESULTS: The positivity rate of DcR3 in HCC tissue was significantly higher than that in juxta-tumour tissue, cirrhosis and normal liver (p = 0.017, p < 0.0001, p < 0.0001, respectively). The positive rate of DcR3 in juxta-tumour and cirrhotic tissue both increased significantly when compared with normal liver tissue (p < 0.0001, p = 0.005, respectively). The positivity rate of DcR3 in HCC in clinical TNM stages I and II was significantly lower than that in stages III and IV (p < 0.0001). The positivity rate of DcR3 in patients without metastasis within 20 months decreased significantly compared with those with metastasis (p < 0.0001). DcR3 expression in patients with alphafoetoprotein levels > or = 400 microg/L, portal vein tumour emboli, capsular infiltration and multicentric tumour was significantly higher than in groups without these features (p = 0.021, p < 0.0001, p < 0.0001, p = 0.002, respectively). CONCLUSION: The overexpression of DcR3 might play an important role in the pathogenesis, progression and metastases of HCC. The DcR3 gene might serve as an important molecular biological indicator in diagnosing and predicting the biological behaviour of patients with HCC.
Pitti RM, Marsters SA, Lawrence DA, et al. Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature. 1998; 396(6712):699-703 [PubMed] Related Publications
Fas ligand (FasL) is produced by activated T cells and natural killer cells and it induces apoptosis (programmed cell death) in target cells through the death receptor Fas/Apol/CD95. One important role of FasL and Fas is to mediate immune-cytotoxic killing of cells that are potentially harmful to the organism, such as virus-infected or tumour cells. Here we report the discovery of a soluble decoy receptor, termed decoy receptor 3 (DcR3), that binds to FasL and inhibits FasL-induced apoptosis. The DcR3 gene was amplified in about half of 35 primary lung and colon tumours studied, and DcR3 messenger RNA was expressed in malignant tissue. Thus, certain tumours may escape FasL-dependent immune-cytotoxic attack by expressing a decoy receptor that blocks FasL.
Bai C, Connolly B, Metzker ML, et al. Overexpression of M68/DcR3 in human gastrointestinal tract tumors independent of gene amplification and its location in a four-gene cluster. Proc Natl Acad Sci U S A. 2000; 97(3):1230-5 [PubMed] Free Access to Full ArticleRelated Publications
Fas-mediated apoptosis is an important regulator of cell survival, and abnormalities in this system have been shown to result in a number of human pathological conditions. A secreted member of the tumor necrosis factor receptor superfamily, DcR3, was recently reported to be amplified in human lung and colon cancers as a negative regulator of Fas-mediated apoptosis. We identified this gene, which we call M68. M68 genomic DNA, mRNA, and protein levels were examined in a series of human gastrointestinal tract tumors. Using M68 immunohistochemistry and a scoring system similar to that used for HER-2/neu, we found that M68 protein was overexpressed in 30 of 68 (44%) human adenocarcinomas of the esophagus, stomach, colon, and rectum. Tumors examined by Northern blot revealed M68 mRNA highly elevated in a similar fraction of primary tumors from the same gastrointestinal tract regions, as well as in the colon adenocarcinoma cell lines SW480 and SW1116. Further, we found M68 protein to be overexpressed in a substantial number of tumors in which gene amplification could not be detected by fluorescence in situ hybridization or quantitative genomic PCR, suggesting that overexpression of M68 may precede amplification in tumors. Finally, we find that M68 lies within a four-gene cluster that includes a novel helicase-like gene (NHL) related to RAD3/ERCC2, a plasma membrane Ras-related GTPase and a member of the stathmin family, amplification or overexpression of which may also contribute to cell growth and tumor progression.
Mild G, Bachmann F, Boulay JL, et al. DCR3 locus is a predictive marker for 5-fluorouracil-based adjuvant chemotherapy in colorectal cancer. Int J Cancer. 2002; 102(3):254-7 [PubMed] Related Publications
Adjuvant chemotherapy reduces the incidence of distant metastasis and increases survival of patients with colorectal cancer. However, predictive markers are needed to define subsets of patients with stage II and III disease that may benefit from adjuvant treatment. A secreted member of the TNF receptor superfamily, the decoy receptor 3 (DcR3), was reported to be amplified in colorectal cancer as a negative regulator of Fas-mediated apoptosis. We analyzed DcR3 gene copy number and protein expression in a large series of tumors from a randomized multicenter trial of 5-fluorouracil/mitomycin C (FU/MMC) adjuvant chemotherapy of the Swiss Group for Clinical Cancer Research (SAKK 40/81), using real-time quantitative PCR and immunohistochemistry on tumor microarrays. Results of gene status and protein expression of DcR3 were correlated with disease-free and overall survival of patients. We observed amplification of the DcR3 gene in 185/294 (63%) and overexpression of the DcR3 protein in 163/223 (73%) of colorectal tumors. Multivariate analysis showed no prognostic effect of DcR3 gene amplification and protein overexpression. However, adjuvant chemotherapy was significantly more beneficial in patients with normal DcR3 gene copy number than in patients with amplification (DFS: HR 2.84, 95% CI 1.16-6.98, p = 0.02; OS: HR 3.15, 95% CI 1.19-8.32, p = 0.02), whereas DcR3 protein overexpression did not influence the effect of adjuvant chemotherapy (DFS: HR 1.02, 95% CI 0.65-1.60, p = 0.95; OS: HR 0.95, 95% CI 0.61-1.49, p = 0.83). We conclude that amplification of the 20q13 locus is a predictive marker for adjuvant chemotherapy in colorectal cancer.
Shen HW, Gao SL, Wu YL, Peng SY Overexpression of decoy receptor 3 in hepatocellular carcinoma and its association with resistance to Fas ligand-mediated apoptosis. World J Gastroenterol. 2005; 11(38):5926-30 [PubMed] Free Access to Full ArticleRelated Publications
AIM: To characterize the expression and genomic amplification of decoy receptor 3 (DcR3) in hepatocellular carcinoma (HCC) and to evaluate the role of DcR3 in apoptosis. METHODS: We examined 48 cases of HCC for DcR3 expression by RT-PCR and DcR3 gene amplification by quantitative genomic PCR. DcR3 protein was detected by immunohistochemistry. Terminal deoxynucleotidyl transferase-mediated dUTP digoxigenin nick and labeling (TUNEL) was used to identify the apoptosis cells in tissues. Primary hepatoma cell culture and MTT test were used to evaluate the protection against FasL- and chemical-induced apoptosis by DcR3 expression. RESULTS: DcR3 mRNA overexpression was detected in 60% HCC (29/48) patients. The occurrence of HCC was not associated with amplification of the gene. One sample base substitution was found in three sites as sequence in Genbank. The expression of DcR3 in HCC was the associatied with the apoptotic index (0.067+/-0.04 vs 0.209+/-0.12, P<0.01), size of mass, stage and infiltration or metastasis (41.2% vs 71.0%, 40% vs 75%, 51.8% vs 84.6%, P<0.05). DcR3 expression could be protect hepatoma cells against apoptosis induced by FasL, but not by chemicals. CONCLUSION: These data suggest that in addition to gene amplification there may be another mechanism underlying DcR3 overexpression. The effect of overexpression of DcR3 on the apoptosis of cancer cells may have direct therapeutic implications for the management of HCC.