Research IndicatorsGraph generated 31 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (9)
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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: TNFRSF10C (cancer-related)
Lung cancer is the most devastating malignancy in the world. Beyond genetic research, epigenomic studies-especially investigations of microRNAs-have grown rapidly in quantity and quality in the past decade. This has enriched our understanding about basic cancer biology and lit up the opportunities for potential therapeutic development. In this review, we summarize the involvement of microRNAs in lung cancer carcinogenesis and behavior, by illustrating the relationship to each cancer hallmark capability, and in addition, we briefly describe the clinical applications of microRNAs in lung cancer diagnosis and prognosis. Finally, we discuss the potential therapeutic use of microRNAs in lung cancer.
Tsikalakis S, Chatziandreou I, Michalopoulos NV, et al.Comprehensive expression analysis of TNF-related apoptosis-inducing ligand and its receptors in colorectal cancer: Correlation with MAPK alterations and clinicopathological associations.
Pathol Res Pract. 2018; 214(6):826-834 [PubMed
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TNF-related, apoptosis-inducing ligand (TRAIL) apoptotic pathway constitutes a promising therapeutic target due to high selectivity and low toxicity of TRAIL targeting agents when administered in combination therapies. 106 colorectal cancers were examined for: relative mRNA expression of TRAIL pathway genes, decoy receptors TRAIL-R3 and TRAIL-R4 promoter methylation and the presence of KRAS, NRAS, BRAF mutations. Elevated mRNA levels were observed in 26%, 15%, 13%, 12% and 10% of the cases for TRAIL-R4, TRAIL-R3, TRAIL-R2, TRAIL-R1 and TRAIL genes respectively. Reduced mRNA levels were detected in 77%, 65%, 64%, 60% and 37% of the cases for TRAIL, TRAIL-R2, TRAIL-R3, TRAIL-R1 and TRAIL-R4 genes respectively. TRAIL-R3 and TRAIL-R4 promoter methylation was detected in 55% and 16% of the analysed samples respectively. TRAIL-R1, TRAIL-R2 elevated relative mRNA levels inversely correlated with tumor stage (p = .036, p = .048). Strong linear correlations of TRAIL receptors' mRNA levels were found: TRAIL-R1/TRAIL-R2 (R = 0.653, p < .001), TRAIL-R2/TRAIL-R3 (R = 0.573, p < .001). Finally, relative expression of TRAIL was correlated with KRAS, BRAF and NRAS mutation status, defining an inverse correlation between increased TRAIL expression and the absence of mutations in Mitogen-activated protein kinase (MAPK) pathway. In conclusion, simultaneous analysis of TRAIL pathway membrane components, pointed towards a significant deregulation of mRNA expression in colorectal tumours. Death receptor overexpression was an indicator of a less aggressive phenotype. The multiple expression patterns of TRAIL pathway components in colorectal tumours underscore the importance of patient selection in order to achieve maximum efficiency with TRAIL targeted therapy.
Lemur tyrosine kinase 3 (LMTK3) is an oncogenic kinase that is involved in different types of cancer (breast, lung, gastric, colorectal) and biological processes including proliferation, invasion, migration, chromatin remodeling as well as innate and acquired endocrine resistance. However, the role of LMTK3 in response to cytotoxic chemotherapy has not been investigated thus far. Using both 2D and 3D tissue culture models, we found that overexpression of LMTK3 decreased the sensitivity of breast cancer cell lines to cytotoxic (doxorubicin) treatment. In a mouse model we showed that ectopic overexpression of LMTK3 decreases the efficacy of doxorubicin in reducing tumor growth. Interestingly, breast cancer cells overexpressing LMTK3 delayed the generation of double strand breaks (DSBs) after exposure to doxorubicin, as measured by the formation of γH2AX foci. This effect was at least partly mediated by decreased activity of ataxia-telangiectasia mutated kinase (ATM) as indicated by its reduced phosphorylation levels. In addition, our RNA-seq analyses showed that doxorubicin differentially regulated the expression of over 700 genes depending on LMTK3 protein expression levels. Furthermore, these genes were found to promote DNA repair, cell viability and tumorigenesis processes / pathways in LMTK3-overexpressing MCF7 cells. In human cancers, immunohistochemistry staining of LMTK3 in pre- and post-chemotherapy breast tumor pairs from four separate clinical cohorts revealed a significant increase of LMTK3 following both doxorubicin and docetaxel based chemotherapy. In aggregate, our findings show for the first time a contribution of LMTK3 in cytotoxic drug resistance in breast cancer.
Bogeas A, Morvan-Dubois G, El-Habr EA, et al.Changes in chromatin state reveal ARNT2 at a node of a tumorigenic transcription factor signature driving glioblastoma cell aggressiveness.
Acta Neuropathol. 2018; 135(2):267-283 [PubMed
] Free Access to Full Article Related Publications
Although a growing body of evidence indicates that phenotypic plasticity exhibited by glioblastoma cells plays a central role in tumor development and post-therapy recurrence, the master drivers of their aggressiveness remain elusive. Here we mapped the changes in active (H3K4me3) and repressive (H3K27me3) histone modifications accompanying the repression of glioblastoma stem-like cells tumorigenicity. Genes with changing histone marks delineated a network of transcription factors related to cancerous behavior, stem state, and neural development, highlighting a previously unsuspected association between repression of ARNT2 and loss of cell tumorigenicity. Immunohistochemistry confirmed ARNT2 expression in cell sub-populations within proliferative zones of patients' glioblastoma. Decreased ARNT2 expression was consistently observed in non-tumorigenic glioblastoma cells, compared to tumorigenic cells. Moreover, ARNT2 expression correlated with a tumorigenic molecular signature at both the tissue level within the tumor core and at the single cell level in the patients' tumors. We found that ARNT2 knockdown decreased the expression of SOX9, POU3F2 and OLIG2, transcription factors implicated in glioblastoma cell tumorigenicity, and repressed glioblastoma stem-like cell tumorigenic properties in vivo. Our results reveal ARNT2 as a pivotal component of the glioblastoma cell tumorigenic signature, located at a node of a transcription factor network controlling glioblastoma cell aggressiveness.
Lu B, Zhou Y, Su Z, et al.Effect of CCL2 siRNA on proliferation and apoptosis in the U251 human glioma cell line.
Mol Med Rep. 2017; 16(3):3387-3394 [PubMed
] Related Publications
Glioma is one of the most common types of tumor of the central nervous system. Increased expression of C‑C motif chemokine 2 (CCL2) has previously been observed in various types of cancer. The effect of CCL2 small interfering (si)RNA on the proliferation, angiogenesis and apoptosis of the glioma cell line U251 was investigated in the present study. Data on CCL2 expression in glioma and normal tissues were obtained from The Cancer Genome Atlas. A total of 30 patients with glioma were enrolled in the present study. Cell proliferation was measured using a Cell Counting kit‑8 assay, while cellular apoptosis and cell cycle distribution were examined using flow cytometric analysis. The reverse transcription‑quantitative polymerase chain reaction and western blot analysis were used to measure the expression levels of biological pathway‑associated proteins caspase‑3, caspase‑7, tumor necrosis factor receptor superfamily member 10C (TNFRSF10C), growth regulated α protein (CXCL1), C‑X‑C motif chemokine 2 (CXCL2), C‑X‑C chemokine receptor type 2 (CXCR2), vascular endothelial growth factor (VEGF)A, VEGFB and VEGF. In addition, the mechanism of cellular apoptosis was analyzed by examining the phosphorylation of extracellular signal‑related kinase (ERK)1/2 and p38 mitogen‑activated protein kinase (p38) in cells treated with the C‑C chemokine receptor type 2 inhibitor RS‑102895. CCL2 was observed to be expressed in the glioma cell line U251 and was inhibited by CCL2 siRNA. Cells transfected with CCL2 siRNA exhibited inhibited cell proliferation, cell cycle arrest and increased cellular apoptosis. The expression levels of the apoptosis‑associated proteins caspase‑3, caspase‑7 and TNFRSF10C were observed to be downregulated, in addition to those of the angiogenesis‑associated proteins CXCL1, CXCL2, CXCR2, VEGFA, VEGFB and VEGF. The decrease in the rate of phosphorylation of ERK1/2 and p38 demonstrated the involvement of the mitogen‑activated protein kinase/ERK pathway in apoptosis. In conclusion, CCL2 siRNA exhibited effective inhibition of cell proliferation and angiogenesis in the glioma cell line U251, which may provide a theoretical basis for the use of CCL2 in in vivo research and clinical treatment as a novel anticancer agent.
Bernardo AR, Cosgaya JM, Aranda A, Jiménez-Lara AMPro-apoptotic signaling induced by Retinoic acid and dsRNA is under the control of Interferon Regulatory Factor-3 in breast cancer cells.
Apoptosis. 2017; 22(7):920-932 [PubMed
] Related Publications
Breast cancer is one of the most lethal malignancies for women. Retinoic acid (RA) and double-stranded RNA (dsRNA) are considered signaling molecules with potential anticancer activity. RA, co-administered with the dsRNA mimic polyinosinic-polycytidylic acid (poly(I:C)), synergizes to induce a TRAIL (Tumor-Necrosis-Factor Related Apoptosis-Inducing Ligand)- dependent apoptotic program in breast cancer cells. Here, we report that RA/poly(I:C) co-treatment, synergically, induce the activation of Interferon Regulatory Factor-3 (IRF3) in breast cancer cells. IRF3 activation is mediated by a member of the pathogen recognition receptors, Toll-like receptor-3 (TLR3), since its depletion abrogates IRF3 activation by RA/poly(I:C) co-treatment. Besides induction of TRAIL, apoptosis induced by RA/poly(I:C) correlates with the increased expression of pro-apoptotic TRAIL receptors, TRAIL-R1/2, and the inhibition of the antagonistic receptors TRAIL-R3/4. IRF3 plays an important role in RA/poly(I:C)-induced apoptosis since IRF3 depletion suppresses caspase-8 and caspase-3 activation, TRAIL expression upregulation and apoptosis. Interestingly, RA/poly(I:C) combination synergizes to induce a bioactive autocrine/paracrine loop of type-I Interferons (IFNs) which is ultimately responsible for TRAIL and TRAIL-R1/2 expression upregulation, while inhibition of TRAIL-R3/4 expression is type-I IFN-independent. Our results highlight the importance of IRF3 and type-I IFNs signaling for the pro-apoptotic effects induced by RA and synthetic dsRNA in breast cancer cells.
Han NN, Zhou Q, Huang Q, Liu KJCarnosic acid cooperates with tamoxifen to induce apoptosis associated with Caspase-3 activation in breast cancer cells in vitro and in vivo.
Biomed Pharmacother. 2017; 89:827-837 [PubMed
] Related Publications
Tamoxifen is known as a standard therapeutic treatment for estrogen receptor-positive breast cancer, which down-regulates breast cancer mortality by 31% approximately. Carnosic acid is a phenolic diterpene, which has anti-cancer, anti-inflammation, anti-diabetic and anti-bacterial properties, generated by various species coming from Lamiaceae family. The breast cancer is reported as one of the most common tumors among women worldwide. In our study, the possible benefits of carnosic acid cooperation with tamoxifen for breast cancer treatment in vitro and in vivo were investigated. Carnosic acid and tamoxifen cooperation led to apoptosis in breast cancer cells. Caspase-3 signaling pathway was promoted for carnosic acid and tamoxifen co-treatment. Consistently, anti-apoptotic molecules Bcl-2 and Bcl-xl were down-regulated, while pro-apoptotic signals Bax and Bad were up-regulated. The elevation of decoy receptor 1 and 2 (DcR1 and DcR2) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) were enhanced for carnosic acid and tamoxifen cooperation. Furthermore, the mouse xenograft model in vivo suggested that carnosic acid and tamoxifen combined therapy inhibited breast cancer growth in comparison to the carnosic acid or tamoxifen monotherapy. Our study supplies a novel therapeutic strategy to induce apoptosis for suppressing breast cancer, which was relied on Caspase-3/TRAIL activation.
Wu J, Li L, Jiang G, et al.B-cell CLL/lymphoma 3 promotes glioma cell proliferation and inhibits apoptosis through the oncogenic STAT3 pathway.
Int J Oncol. 2016; 49(6):2471-2479 [PubMed
] Related Publications
Aberrant expression of oncogenes and/or tumor suppressors play fundamental roles in the pathogenesis of glioma. B-cell CLL/lymphoma 3 (BCL3) was previously found to be a putative proto-oncogene in human cancers and the decoy receptor DcR1 is induced in a p50/Bcl3-dependent manner and attenuates the efficacy of temozolomide in glioblastoma cells. However, its expression status, clinical significance and biological functions in glioma remain largely unknown. In the present study, the levels of BCL3 were overexpressed in glioma compared to normal brain tissues. Furthermore, high expression of BCL3 protein was confirmed by immunoblotting in glioma cells as compared with normal human astrocyte cell line. The positive expression of BCL3 was correlated with adverse prognostic features and reduced overall survival rate of glioma patients. BCL3 silencing resulted in prominent decreased proliferation, cell cycle arrest in G1 phase and increased apoptosis in U251 cells. In contrast, BCL3 overexpression in U87 cells remarkably facilitated proliferative ability and cell cycle progression and induced apoptosis. In vivo studies showed that BCL3 knockdown inhibited the tumor growth of U251 cells in a mouse xenograft model. Mechanistically, BCL3 positively regulated the abundance of STAT3, p-STAT3 and the downstream targets of STAT3 pathway including BCL2, MCL-1 and cyclin D1 in glioma cells. Furthermore, a positive correlation between BCL3 and STAT3 expression was observed in glioma specimens. Notably, we confirmed that STAT3 knockdown abolished the oncogenic roles of BCL3 in glioma. In conclusion, we suggest that BCL3 serves as an oncogene in glioma by modulating proliferation, cell cycle progression and apoptosis, and its oncogenic effects are mediated by the STAT3 signaling pathway.
Ouyang W, Zhang S, Yang B, et al.β-catenin is regulated by USP9x and mediates resistance to TRAIL-induced apoptosis in breast cancer.
Oncol Rep. 2016; 35(2):717-24 [PubMed
] Related Publications
To investigate the regulatory mechanisms of decoy receptor expression in TRAIL-resistant breast cancer MCF-7 cells, cytotoxicity and apoptosis assays were applied to examine sensitivity to TRAIL in breast cancer cells. Immunofluorescence and immunoprecipitation were used to detect the co-localization and interaction of USP9x and β-catenin. Luciferase assay was used to examine activity of the DcR1/DcR2/OPG reporter. Overexpression/silencing of β-catenin was performed to confirm β-catenin mediated transcription of the decoy receptors. Additionally, silencing of USP9x was performed to prove that USP9X stabilizes β-catenin and mediates TRAIL-resistance. It was found that USP9x interacted with β-catenin and inhibited the degradation of β-catenin through the deubiquitination of β-catenin. Luciferase reporter assays showed induction of DcR1/DcR2/OPG reporter activity observed upon co-transfection of β-catenin and Tcf-4. The overexpression/silencing of β-catenin further confirmed the role of β-catenin in the regulation of transcription of the decoy receptors. Silencing of USP9x directly evidenced that USP9x affected the protein expression level of β-catenin, the transcription level of the decoy receptors, and reversed TRAIL-resistance of MCF-7 cells. In conclusion, USP9x interacted with and stabilized β-catenin through deubiquitination to mediate transcription of the decoy receptors in breast cancer cells. Our results offer new insights into the mechanisms of resistance to TRAIL, and USP9x could potentially be a therapeutic target for TRAIL-resistant breast cancers.
Narayan G, Xie D, Ishdorj G, et al.Epigenetic inactivation of TRAIL decoy receptors at 8p12-21.3 commonly deleted region confers sensitivity to Apo2L/trail-Cisplatin combination therapy in cervical cancer.
Genes Chromosomes Cancer. 2016; 55(2):177-89 [PubMed
] Related Publications
Multiple chromosomal regions are affected by deletions in cervical cancer (CC) genomes, but their consequence and target gene involvement remains unknown. Our single nucleotide polymorphism (SNP) array identified 8p copy number losses localized to an 8.4 Mb minimal deleted region (MDR) in 36% of CC. The 8p MDR was associated with tumor size, treatment outcome, and with multiple HPV infections. Genetic, epigenetic, and expression analyses of candidate genes at MDR identified promoter hypermethylation and/or inactivation of decoy receptors TNFRSF10C and TNFRSF10D in the majority of CC patients. TNFRSF10C methylation was also detected in precancerous lesions suggesting that this change is an early event in cervical tumorigenesis. We further demonstrate here that CC cell lines exhibiting downregulated expression of TNFRSF10C and/or TNFRSF10D effectively respond to TRAIL-induced apoptosis and this affect was synergistic in combination with DNA damaging chemotherapeutic drugs. We show that the CC cell lines harboring epigenetic inactivation of TRAIL decoy receptors effectively activate downstream caspases suggesting a critical role of inactivation of these genes in efficient execution of extrinsic apoptotic pathway and therapy response. Therefore, these findings shed new light on the role of genetic/epigenetic defects in TRAIL decoy receptor genes in the pathogenesis of CC and provide an opportunity to explore strategies to test decoy receptor gene inactivation as a biomarker of response to Apo2L/TRAIL-combination therapy.
Sriraksa R, Limpaiboon TTRAIL in Combination with Subtoxic 5-FU Effectively Inhibit Cell Proliferation and Induce Apoptosis in Cholangiocarcinoma Cells.
Asian Pac J Cancer Prev. 2015; 16(16):6991-6 [PubMed
] Related Publications
In the past decade, the incidence and mortality rates of cholangiocarcinoma (CCA) have been increasing worldwide. The relatively low responsiveness of CCA to conventional chemotherapy leads to poor overall survival. Recently, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or Apo2L) has emerged as the most promising anti-cancer therapeutic agent since it is able to selectively induce apoptosis of tumor cells but not normal cells. In this study, we aimed to investigate the therapeutic effect of TRAIL in CCA cell lines (M213, M214 and KKU100) compared with the immortal biliary cell line, MMNK1, either alone or in combination with a subtoxic dose of 5-fluorouracil (5-FU). We found that recombinant human TRAIL (rhTRAIL) was a potential agent which significantly inhibited cell proliferation and mediated caspase activities (caspases 8, 9 and 3/7) and apoptosis of CCA cells. The combined treatment of rhTRAIL and 5-FU effectively enhanced inhibition of CCA cell growth with a smaller effect on MMNK1. Our finding suggests TRAIL to be a novel anti-cancer therapeutic agent and advantage of its combination with a conventional chemotherapeutic drug for effective treatment of CCA.
Lit BM, Kwong YL, Wong KFImmunohistochemical detection of cytoplasmic nucleophosmin in formalin-fixed paraffin-embedded marrow trephine biopsies in acute myeloid leukaemia.
J Clin Pathol. 2016; 69(5):409-14 [PubMed
] Related Publications
AIMS: Nucleophosmin (NPM1) gene mutations resulting in cytoplasmic delocalisation of nucleophosmin (NPMc+) are the most common genetic abnormality in acute myeloid leukaemia (AML). In this study, we tested whether immunohistochemical (IHC) detection of cytoplasmic NPM1 (cNPM1) in formalin-fixed bone marrow trephine biopsies correlated with NPM1 mutations and the prognostic impact of NPM1 and fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) gene mutations was also assessed.
METHODS: A total of 71 Chinese adult de novo AML cases were evaluated for cNPM1 by IHC where the bone marrow trephines were fixed in 10% buffered formalin and decalcified by 5% EDTA. NPM1 and FLT3-ITD gene mutations were also investigated using PCR, fragment analysis and direct DNA sequencing.
RESULTS: IHC analysis of cNPM1 had a very good sensitivity (86.7%) and excellent specificity (96.4%) for NPM1 mutation. The positive predictive value was 86.7% and the negative predictive value was 96.4%. NPM1 mutations and FLT3-ITD were closely associated (p = 0.003). Patients with mutated NPM1 and without FLT3-ITD mutation have a longer overall survival (p = 0.042) than patients with both NPM1 and FLT3-ITD mutations.
CONCLUSIONS: Our results showed that IHC detection of cNPM1 in formalin-fixed trephine biopsies correlated well but not entirely with NPM1 mutation. Furthermore, NPM1 mutations were significantly more frequent in FLT3-ITD than FLT3-wild-type cases.
Temozolomide is used widely to treat malignant glioma, but the overall response to this agent is generally poor. Resistance to DNA-damaging drugs such as temozolomide has been related to the induction of antiapoptotic proteins. Specifically, the transcription factor NF-κB has been suggested to participate in promoting the survival of cells exposed to chemotherapy. To identify factors that modulate cytotoxicity in the setting of DNA damage, we used an unbiased strategy to examine the NF-κB-dependent expression profile induced by temozolomide. By this route, we defined the decoy receptor DcR1 as a temozolomide response gene induced by a mechanism relying upon p50/NF-κB1. A conserved NF-κB-binding sequence (κB-site) was identified in the proximal promoter and was demonstrated to be required for DcR1 induction by temozolomide. Loss-of-function and gain-of-function studies reveal that the atypical IκB protein, Bcl3, is also required for induction of DcR1 by temozolomide. Mechanistically, DcR1 attenuates temozolomide efficacy by blunting activation of the Fas receptor pathway in p53(+/+) glioma cells. Intracranial xenograft studies show that DcR1 depletion in glioma cells enhances the efficacy of temozolomide. Taken together, our results show how DcR1 upregulation mediates temozolomide resistance and provide a rationale for DcR1 targeting as a strategy to sensitize gliomas to this widely used chemotherapy.
Woo JK, Kang JH, Jang YS, et al.Evaluation of preventive and therapeutic activity of novel non-steroidal anti-inflammatory drug, CG100649, in colon cancer: Increased expression of TNF-related apoptosis-inducing ligand receptors enhance the apoptotic response to combination treatment with TRAIL.
Oncol Rep. 2015; 33(4):1947-55 [PubMed
] Related Publications
Non-steroidal anti-inflammatory drugs (NSAIDs) have been suggested as the potential new class of preventive or therapeutic antitumor agents. The aim of the present study was to evaluate the antitumor activity of the novel NSAID, CG100649. CG100649 is a novel NSAID dual inhibitor for COX-2 and carbonic anhydrase (CA)-I/-II. In the present study, we investigated the alternative mechanism by which CG100649 mediated suppression of the colon cancer growth and development. The anchorage‑dependent and -independent clonogenic assay showed that CG100649 inhibited the clonogenicity of human colon cancer cells. The flow cytometric analysis showed that CG100649 induced the G2/M cell cycle arrest in colon cancer cells. Animal studies showed that CG100649 inhibited the tumor growth in colon cancer xenograft in nude mice. Furthermore, quantitative PCR and FACS analysis demonstrated that CG100649 upregulated the expression of TNF-related apoptosis-inducing ligand (TRAIL) receptors (DR4 and DR5) but decreased the expression of decoy receptors (DcR1 and DcR2) in colon cancer cells. The results showed that CG100649 treatment sensitized TRAIL‑mediated growth suppression and apoptotic cell death. The combination treatment resulted in significant repression of the intestinal polyp formation in APCmin/+ mice. Our data clearly demonstrated that CG100649 contains preventive and therapeutic activity for colon cancer. The present study may be useful for identification of the potential benefit of the NSAID CG100649, for the achievement of a better treatment response in colon cancer.
Verim A, Turan S, Farooqi AA, et al.Association between laryngeal squamous cell carcinoma and polymorphisms in tumor necrosis factor related apoptosis induce ligand (TRAIL), TRAIL receptor and sTRAIL levels.
Asian Pac J Cancer Prev. 2014; 15(24):10697-703 [PubMed
] Related Publications
The laryngeal squamous cell carcinoma (LSCC) is one of the most common malignant tumors occurring in the head and neck. Tumor necrosis factor related apoptosis induce ligand (TRAIL) and TRAIL-receptors (DR4, DR5, DcR1, DcR2) are known as important members of TRAIL-mediated biochemical signaling pathway. Associations between polymorphisms in these genes and clinicopathological characteristics of human laryngeal carcinoma are not well defined. This study therefore aimed to investigate a possible relationship among the TRAIL and TRAIL-DR4 polymorphisms and sTRAIL levels in the risk or progression of LSCC. A total of 99 patients with laryngeal cancer and 120 healthy subjects were enrolled in the study. DR4 C626G and TRAIL 1595 C/T genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis and sTRAIL levels were measured by ELISA. There were significant differences in the distribution of DR4 C626G genotypes and frequencies of the alleles between laryngeal cancer patients and controls (p<0.001) but not in TRAIL 1595 C/T. We found the increased frequency of the DR4 C626G homozygote CC genotype in patients than in controls (p<0.001). Haplotype analysis revealed that there was also a statistically significant relationship between TRAIL and TRAIL-DR4 polymorphisms and laryngeal cancer. Serum sTRAIL levels in the laryngeal patients with CC genotype who had advanced tumour stage were lower than those of patients with early tumor stage (p=0.014). Our findings suggest that DR4 C626G genotypes and sTRAIL levels might be associated with progression of laryngeal cancer in the Turkish population.
Current treatment modalities for pancreatic carcinoma afford only modest survival benefits. TRAIL, as a potent and specific inducer of apoptosis in cancer cells, would be a promising new treatment option. However, since not all pancreatic cancer cells respond to TRAIL, further improvements and optimizations are still needed. One strategy to improve the effectiveness of TRAIL-based therapies is to specifically target one of the 2 cell death inducing TRAIL-receptors, TRAIL-R1 or TRAIL-R2 to overcome resistance. To this end, we designed constructs expressing soluble TRAIL (sTRAIL) variants that were rendered specific for either TRAIL-R1 or TRAIL-R2 by amino acid changes in the TRAIL ectodomain. When we expressed these constructs, including wild-type sTRAIL (sTRAIL(wt)), TRAIL-R1 (sTRAIL(DR4)) and TRAIL-R2 (sTRAIL(DR5)) specific variants, in 293 producer cells we found all to be readily expressed and secreted into the supernatant. These supernatants were subsequently transferred onto target cancer cells and apoptosis measured. We found that the TRAIL-R1 specific variant had higher apoptosis-inducing activity in human pancreatic carcinoma Colo357 cells as well as PancTu1 cells that were additionally sensitized by targeting of XIAP. Finally, we tested TRAIL-R1 specific recombinant TRAIL protein (rTRAIL(DR4)) on Colo357 xenografts in nude mice and found them to be more efficacious than rTRAIL(wt). Our results demonstrate the benefits of synthetic biological approaches and show that TRAIL-R1 specific variants can potentially enhance the therapeutic efficacy of TRAIL-based therapies in pancreatic cancer, suggesting that they can possibly become part of individualized and tumor specific combination treatments in the future.
The tumor necrosis factor (TNF)-related apoptosis-inducing ligand- receptor (TRAIL-R) family has emerged as a key mediator of cell fate and survival. Ligation of TRAIL ligand to TRAIL-R1 or TRAIL-R2 initiates the extrinsic apoptotic pathway characterized by the recruitment of death domains, assembly of the death-inducing signaling complex (DISC), caspase activation and ultimately apoptosis. Conversely the decoy receptors TRAIL-R3 and TRAIL-R4, which lack the pro-apoptotic death domain, function to dampen the apoptotic response by competing for TRAIL ligand. The tissue restricted expression of the decoy receptors on normal but not cancer cells provides a therapeutic rational for the development of selective TRAIL-mediated anti-tumor therapies. Recent clinical trials using agonistic antibodies against the apoptosis-inducing TRAIL receptors or recombinant TRAIL have been promising; however the number of patients in complete remission remains stubbornly low. The mechanisms of TRAIL resistance are relatively unexplored but may in part be due to TRAIL-R down-regulation or shedding of TRAIL-R by tumor cells. Therefore a better understanding of the mechanisms underlying TRAIL resistance is required. The ubiquitin-proteasome system (UPS) has been shown to regulate TRAIL-R members suggesting that pharmacological inhibition of the UPS may be a novel strategy to augment TRAIL-based therapies and increase efficacies. We recently identified b-AP15 as an inhibitor of proteasome deubiquitinase (DUB) activity. Interestingly, exposure of tumor cell lines to b-AP15 resulted in increased TRAIL-R2 expression and enhanced sensitivity to TRAIL-mediated apoptosis and cell death in vitro and in vivo. In conclusion, targeting the UPS may represent a novel strategy to increase the cell surface expression of pro-apoptotic TRAIL-R on cancer cells and should be considered in clinical trials targeting TRAIL-receptors in cancer patients.
Dauksa A, Gulbinas A, Endzinas Z, et al.DNA methylation at selected CpG sites in peripheral blood leukocytes is predictive of gastric cancer.
Anticancer Res. 2014; 34(10):5381-8 [PubMed
] Related Publications
BACKGROUND/AIM: Recently, a set of studies addressed the question of the prevalence of aberrant methylation in surrogate tissues, such as peripheral blood leukocytes. Toward this aim, we conducted a case-control pilot study to investigate aberrant methylation in leukocytes of gastric cancer patients.
MATERIALS AND METHODS: The SNuPE combined with ion pair reverse phase HPLC (SIRPH method) was used to examine site-specific methylation status at selected CpG sites of the promoter regions of APC, ACIN1, BCL2, CD44, DAPK1, CDKN2A, RARB, TNFRSF10C HS3ST2 and of LINE-1, Alu repeats.
RESULTS: We observed that in the patients, tumor suppressor genes were slightly but significantly higher methylated at several CpG sites, while DNA repetitive elements were slightly less methylated compared to controls. This was found to be significantly associated with higher prevalence for gastric cancer.
CONCLUSION: These results suggest that larger studies must be carried-out to explore the biological significance and clinical usefulness of leukocyte DNA as non-invasive detection tool for gastric cancer.
Xu Y, Zhang H, Lit LC, et al.The kinase LMTK3 promotes invasion in breast cancer through GRB2-mediated induction of integrin β₁.
Sci Signal. 2014; 7(330):ra58 [PubMed
] Related Publications
Lemur tyrosine kinase 3 (LMTK3) is associated with cell proliferation and endocrine resistance in breast cancer. We found that, in cultured breast cancer cell lines, LMTK3 promotes the development of a metastatic phenotype by inducing the expression of genes encoding integrin subunits. Invasive behavior in various breast cancer cell lines positively correlated with the abundance of LMTK3. Overexpression of LMTK3 in a breast cancer cell line with low endogenous LMTK3 abundance promoted actin cytoskeleton remodeling, focal adhesion formation, and adhesion to collagen and fibronectin in culture. Using SILAC (stable isotope labeling by amino acids in cell culture) proteomic analysis, we found that LMTK3 increased the abundance of integrin subunits α5 and β1, encoded by ITGA5 and ITGB1. This effect depended on the CDC42 Rho family guanosine triphosphatase, which was in turn activated by the interaction between LMTK3 and growth factor receptor-bound protein 2 (GRB2), an adaptor protein that mediates receptor tyrosine kinase-induced activation of RAS and downstream signaling. Knockdown of GRB2 suppressed LMTK3-induced CDC42 activation, blocked ITGA5 and ITGB1 expression promoted by the transcription factor serum response factor (SRF), and reduced invasive activity. Furthermore, abundance of LMTK3 positively correlated with that of the integrin β1 subunit in breast cancer patient's tumors. Our findings suggest a role for LMTK3 in promoting integrin activity during breast cancer progression and metastasis.
Kang KW, Lee MJ, Song JA, et al.Overexpression of goosecoid homeobox is associated with chemoresistance and poor prognosis in ovarian carcinoma.
Oncol Rep. 2014; 32(1):189-98 [PubMed
] Related Publications
Ovarian carcinoma is the most lethal cancer among all gynecological malignancies due to recurrence through chemoresistance. The aim of the present study was to identify new biomarkers to predict chemoresistance and prognosis in ovarian carcinomas. The mRNA expression by qRT-PCR was examined in 60 ovarian serous carcinomas for selected genes from the screening by PCR array focusing on apoptosis, epithelial-to-mesenchymal transition and cancer pathways. The clinical impact was assessed by analyzing the correlation between gene expression and clinicopathological variables. Further validation with immunohistochemistry was performed with 75 cases of serous carcinomas. The chemoresistance was significantly associated with high expression of FOS, GSC, SNAI1, TERT and TNFRSF10D, and low expression of CDKN1A, TNFRSF10A, TNFRSF10C and TRAF1 (p<0.05, t-test). Low expression of TRAF1 and high expression of E2F1, FOS, TERT and GSC were significantly associated with advanced clinical stage (p<0.05, χ2-test). Lymph node metastasis was significantly associated with high expression of GSC. The upregulation group of TERT, GSC, NOTCH1 and SNAI1, and downregulation group of TRAF1 were significantly associated with poor overall survival (p<0.05, log-rank test). On further validation with immunohistochemistry, overexpression of goosecoid homeobox (GSC) was associated with poor overall survival. The results suggest that GSC is the most potential biomarker of drug response and poor prognosis in ovarian serous carcinomas.
Constitutional epigenetic changes detected in blood or non-disease involving tissues have been associated with disease susceptibility. We measured promoter methylation of CDKN2A (p16 and p14ARF) and 13 melanoma-related genes using bisulfite pyrosequencing of blood DNA from 114 cases and 122 controls in 64 melanoma-prone families (26 segregating CDKN2A germline mutations). We also obtained gene expression data for these genes using microarrays from the same blood samples. We observed that CDKN2A epimutation is rare in melanoma families, and therefore is unlikely to cause major susceptibility in families without CDKN2A mutations. Although methylation levels for most gene promoters were very low (<5%), we observed a significantly reduced promoter methylation (odds ratio = 0.63, 95% confidence interval = 0.50, 0.80, P<0.001) and increased expression (fold change = 1.27, P = 0.048) for TNFRSF10C in melanoma cases. Future research in large prospective studies using both normal and melanoma tissues is required to assess the significance of TNFRSF10C methylation and expression changes in melanoma susceptibility.
Kuo CC, Lin CY, Shih YL, et al.Frequent methylation of HOXA9 gene in tumor tissues and plasma samples from human hepatocellular carcinomas.
Clin Chem Lab Med. 2014; 52(8):1235-45 [PubMed
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BACKGROUND: Aberrant DNA methylation is associated with the development of hepatocellular carcinoma (HCC), suggesting that gene methylation could be a potential biomarker for detection of HCC. The aim of this study is to identify potential biomarkers in HCC.
METHODS: We used the Infinium methylation array and a DNA-pooling strategy to analyze the genome-wide methylation profile in HCC. Quantitative methylation-specific PCR (Q-MSP) was used to validate homeobox A9 (HOXA9) methylation in 29 normal controls, 100 HCC samples and adjacent non-tumor tissues and in 74 plasma samples, including 40 patients with HCC.
RESULTS: Ten genes (HOXA9, NEUROG1, TNFRSF10C, IRAK3, GFPT2, ZNF177, DPYSL4, ELOVL4, FSD1, and CACNA1G) showed differences in methylation between controls and HCCs. Of these, HOXA9 was significantly hypermethylated in HCCs (76.7%; 23/30) compared with controls (3.4%; 1/29). In addition, combination analysis of two- and three-gene sets for HCC detection showed greater sensitivity (90%-96.7%) and comparable specificity (93.1%-96.6%) to each individual gene (33.3%-76.7% and 55.2%-100.0%). HOXA9 methylation was further validated by Q-MSP in two independent set of clinical samples including 100 HCC and paired non-tumor tissues. Further, HOXA9 methylation could be detected in plasma from HCC patients (n=40) but not in normal plasma (n=34) (p<0.0005). Combined testing (either parameter positive) for α-fetoprotein (AFP, a plasma protein biomarker) and HOXA9 methylation showed greater sensitivity (94.6%) for detection of HCC than AFP alone (75.7%).
CONCLUSIONS: These data suggest that methylation of HOXA9 could be a helpful biomarker to assist in HCC detection.
Stamatelli A, Vlachou C, Aroni K, et al.Epigenetic alterations in sporadic basal cell carcinomas.
Arch Dermatol Res. 2014; 306(6):561-9 [PubMed
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Basal cell carcinoma (BCC) is the most common malignant human neoplasm characterized by slow growth and virtual absence of metastases. Recently, it has become evident that along with genetic mutations epigenetic alterations play a key role in the pathogenesis of human cancer. We searched for promoter methylation of hMLH1, RASSF1A, DAPK, APC, DCR1 and DCR2 genes and BRAF mutations in BCCs in association with the clinicopathological parameters and the histological subtypes of the tumours. Fifty-two BCCs, 17 FFPE along with 35 fresh tissue samples with matching normal tissues for 26 cases were analyzed by methylation-specific PCR to assess the methylation status of hMLH1, RASSF1A, DAPK, APC, DCR1 and DCR2 genes after sodium bisulfite treatment of the tumour and normal DNA. hMLH1 and DCR1 gene expression was investigated by immunohistochemistry. BRAF mutations were studied by high resolution melting analysis. Methylation was detected at a variable frequency of 44, 33, 32.5, 32 and 14 % of DCR2, APC, DCR1, RASSF1 and DAPK promoters, respectively, whereas methylation of hMLH1 promoter was absent. No BRAF mutations were found. There was no correlation between the frequency of the promoter methylation of the above-mentioned genes and the clinicopathological features or the histological subtypes of the tumours. The relatively high frequency of RASSF1A, DCR1, DCR2 and APC promoter methylation may imply that methylation constitutes an important pathway in the tumourigenesis of BCC that could provide new opportunities in developing epigenetic therapies for BCC patients. Nevertheless, further studies are needed to establish the above-mentioned hypothesis.
Takeuchi A, Shiota M, Beraldi E, et al.Insulin-like growth factor-I induces CLU expression through Twist1 to promote prostate cancer growth.
Mol Cell Endocrinol. 2014; 384(1-2):117-25 [PubMed
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Clusterin (CLU) is cytoprotective molecular chaperone that is highly expressed in castrate-resistant prostate cancer (CRPC). CRPC is also characterized by increased insulin-like growth factor (IGF)-I responsiveness which induces prostate cancer survival and CLU expression. However, how IGF-I induces CLU expression and whether CLU is required for IGF-mediated growth signaling remain unknown. Here we show that IGF-I induced CLU via STAT3-Twist1 signaling pathway. In response to IGF-I, STAT3 was phosphorylated, translocated to the nucleus and bound to the Twist1 promoter to activate Twist1 transcription. In turn, Twist1 bound to E-boxes on the CLU promoter and activated CLU transcription. Inversely, we demonstrated that knocking down Twist1 abrogated IGF-I induced CLU expression, indicating that Twist1 mediated IGF-I-induced CLU expression. When PTEN knockout mice were crossed with lit/lit mice, the resultant IGF-I deficiency suppressed Twist1 as well as CLU gene expression in mouse prostate glands. Moreover, both Twist1 and CLU knockdown suppressed prostate cancer growth accelerated by IGF-I, suggesting the relevance of this signaling not only in an in vitro, but also in an in vivo. Collectively, this study indicates that IGF-I induces CLU expression through sequential activation of STAT3 and Twist1, and suggests that this signaling cascade plays a critical role in prostate cancer pathogenesis.
Schiano C, Casamassimi A, Rienzo M, et al.Involvement of Mediator complex in malignancy.
Biochim Biophys Acta. 2014; 1845(1):66-83 [PubMed
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Mediator complex (MED) is an evolutionarily conserved multiprotein, fundamental for growth and survival of all cells. In eukaryotes, the mRNA transcription is dependent on RNA polymerase II that is associated to various molecules like general transcription factors, MED subunits and chromatin regulators. To date, transcriptional machinery dysfunction has been shown to elicit broad effects on cell proliferation, development, differentiation, and pathologic disease induction, including cancer. Indeed, in malignant cells, the improper activation of specific genes is usually ascribed to aberrant transcription machinery. Here, we focus our attention on the correlation of MED subunits with carcinogenesis. To date, many subunits are mutated or display altered expression in human cancers. Particularly, the role of MED1, MED28, MED12, CDK8 and Cyclin C in cancer is well documented, although several studies have recently reported a possible association of other subunits with malignancy. Definitely, a major comprehension of the involvement of the whole complex in cancer may lead to the identification of MED subunits as novel diagnostic/prognostic tumour markers to be used in combination with imaging technique in clinical oncology, and to develop novel anti-cancer targets for molecular-targeted therapy.
The TNF-related apoptosis-inducing ligand (TRAIL) is a TNF family member which has been under intense focus because of its remarkable ability to induce apoptosis in malignant human cells while leaving normal cells unscathed. However, many cancer cells remain resistant to TRAIL. In this study, we had investigated the synergistic effects of low dose fluorouracil (5-Fu) and TRAIL on TRAIL-resistant human gastric adenocarcinoma AGS cells and explored the potential mechanisms. Cell viability was analyzed by sulforhodamine B (SRB) assay and the synergistic effects were evaluated by Jin's formula and confirmed by both morphological changes under inverted microscope and flow cytometry. The expression of TRAIL-R1 (death receptor 4, DR4), TRAIL-R2 (DR5), TRAIL-R3 (decoy receptor, DcR1), TRAIL-R4 (DcR2), procaspase-3, procaspase-8, and procaspase-9 was detected by western blotting. Our results showed that there were significant synergistic effects of low dose 5-Fu and TRAIL on TRAIL-resistant AGS cells, and this effect was supposed to be mediated by decreasing DcR2 expression and increasing DR5 expression. The extrinsic and intrinsic apoptosis pathways were both activated. The data suggest that combined treatment of low dose 5-Fu and TRAIL can be an effective therapeutic approach for gastric adenocarcinoma.
Di Carli M, Tanno B, Capodicasa C, et al.Proteome changes induced by c-myb silencing in human chronic myeloid leukemia cells suggest molecular mechanisms and putative biomarkers of hematopoietic malignancies.
J Proteomics. 2014; 96:200-22 [PubMed
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UNLABELLED: To shed light on the molecular mechanisms associated with aberrant accumulation of c-Myb in chronic myeloid leukemia, comparative proteomic analysis was performed on c-myb RNAi-specifically silenced K562 cells, sampled on a time-course basis. 2D-DIGE technology highlighted 37 differentially-represented proteins that were further characterized by nLC-ESI-LIT-MS/MS and validated by western blotting and qRT-PCR analysis. Most of the deregulated proteins were related to protein folding, energy/primary metabolism, transcription/translation regulation and oxidative stress response. Protein network analysis suggested that glycolysis, gluconeogenesis and protein ubiquitination biosynthesis pathways were highly represented, confirming also the pivotal role of c-Myc. A specific reduced representation was observed for glyceraldehyde-3-phosphate-dehydrogenase and α-enolase, suggesting a possible role of c-Myb in the activation of aerobic glycolysis. A reduced amount was also observed for stress responsive heat shock 70kDa protein and 78kDa glucose-regulated protein, previously identified as direct targets of c-Myb. Among over-represented proteins, worth mentioning is the chromatin modifier chromobox protein homolog 3 that contributes to silencing of E2F- and Myc-responsive genes in quiescent G0 cells. Data here presented, while providing novel insights onto the molecular mechanisms underlying c-Myb activity, indicate potential protein biomarkers for monitoring the progression of chronic myeloid leukemia.
BIOLOGICAL SIGNIFICANCE: Myeloid leukemia is a malignant disease of the hematopoietic system in which cells of myeloid lineages accumulate to an undifferentiated state. In particular, it was shown that an aberrant accumulation of the c-Myb transcriptional factor is associated with the suppression of normal differentiation processes promoting the development of the hematopoietic malignancies. Many efforts have been recently made to identify novel genes directly targeted by c-Myb at a transcriptome level. In this work, we originally describe a differential proteomic approach to facilitate the comprehension of the regulation of the protein networks exerted by c-Myb. Our study reveals a complex network of proteins regulated by c-Myb. The functional heterogeneity of these proteins emphasizes the pleiotropic role of c-Myb as a regulator of genes that are crucial for energy production and stress response in leukemia. In fact, variations in glyceraldehyde-3-phosphate-dehydrogenase and α-enolase suggest a possible role of c-Myb in the activation of aerobic glycolysis. Moreover, significant differences were found for heat shock 70kDa protein and 78kDa glucose-regulated protein known as direct c-Myb targets. This work highlights potential protein biomarkers to look into disease progression and to develop translational medicine approaches in myeloid leukemia.
Ng EK, Li R, Shin VY, et al.MicroRNA-143 is downregulated in breast cancer and regulates DNA methyltransferases 3A in breast cancer cells.
Tumour Biol. 2014; 35(3):2591-8 [PubMed
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MicroRNAs (miRNAs) are small non-protein-coding RNAs that regulate expression of a wide variety of genes including those involved in cancer development. Here, we investigate the role of miR-143 in breast cancer. In this study, we showed that miR-143 was frequently downregulated in 80% of breast carcinoma tissues compared to their adjacent noncancerous tissues. Ectopic expression of miR-143 inhibited proliferation and soft agar colony formation of breast cancer cells and also downregulated DNA methyltransferase 3A (DNMT3A) expression on both mRNA and protein levels. Restoration of miR-143 expression in breast cancer cells reduces PTEN hypermethylation and increases TNFRSF10C methylation. DNMT3A was demonstrated to be a direct target of miR-143 by luciferase reporter assay. Furthermore, miR-143 expression was observed to be inversely correlated with DNMT3A mRNA and protein expression in breast cancer tissues. Our findings suggest that miR-143 regulates DNMT3A in breast cancer cells. These findings elucidated a tumor-suppressive role of miR-143 in epigenetic aberration of breast cancer, providing a potential development of miRNA-based treatment for breast cancer.
Venza M, Visalli M, Catalano T, et al.Impact of DNA methyltransferases on the epigenetic regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor expression in malignant melanoma.
Biochem Biophys Res Commun. 2013; 441(4):743-50 [PubMed
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Aberrant promoter methylation and resultant silencing of TRAIL decoy receptors were reported in a variety of cancers, but to date little is known about the relevance of this epigenetic modification in melanoma. In this study, we examined the methylation and the expression status of TRAIL receptor genes in cutaneous and uveal melanoma cell lines and specimens and their interaction with DNA methyltransferases (DNMTs) DNMT1, DNMT3a, and DNMT3b. DR4 and DR5 methylation was not frequent in cutaneous melanoma but on the contrary it was very frequent in uveal melanoma. No correlation between methylation status of DR4 and DR5 and gene expression was found. DcR1 and DcR2 were hypermethylated with very high frequency in both cutaneous and uveal melanoma. The concordance between methylation and loss of gene expression ranged from 91% to 97%. Here we showed that DNMT1 was crucial for DcR2 hypermethylation and that DNMT1 and DNMT3a coregulate the methylation status of DcR1. Our work also revealed the critical relevance of DcR1 and DcR2 expression in cell growth and apoptosis either in cutaneous or uveal melanoma. In conclusion, the results presented here claim for a relevant impact of aberrant methylation of decoy receptors in melanoma and allow to understand how the silencing of DcR1 and DcR2 is related to melanomagenesis.
Braga Lda C, Silva LM, Piedade JB, et al.Epigenetic and expression analysis of TRAIL-R2 and BCL2: on the TRAIL to knowledge of apoptosis in ovarian tumors.
Arch Gynecol Obstet. 2014; 289(5):1061-9 [PubMed
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OBJECTIVE: This study assesses TRAIL-R2 (TNF-related apoptosis-inducing ligand receptor 2) and BCL2 (B cell CLL/lymphoma 2) expression as well as CpG island methylation within the TRAIL-R2 promoter in ovarian serous tumors and primary and metastatic serous EOC (epithelial ovarian cancer).
METHODS: RNA and DNA were obtained from women with normal ovarian tissues (n = 18), ovarian serous cystadenoma tumors (n = 11) and serous EOC (n = 16) using Trizol®. Quantitative PCR was performed to quantify the relative levels of TRAIL-R2 and BCL2. The methylation frequency of the TRAIL-R3 promoter was assessed using a methylation-specific PCR assay after DNA bisulfite conversion. Differences between the groups were evaluated using the χ (2), Mann-Whitney U or Kruskal-Wallis tests, as indicated.
RESULTS: We identified TRAIL-R2 and BCL2 mRNA expressed in all ovarian tumor groups, and there were significant differences between the groups. Both genes had low expression levels in ovarian serous cystadenoma and primary EOC tumors when compared with metastatic EOC. Methylation of the TRAIL-R2 promoter was frequently observed in all groups; however, there were no statistically significant associations.
CONCLUSIONS: Primary EOC is associated with lower TRAIL-R2 and BCL2 expression levels, while metastatic EOC is associated with higher expression of these genes. Promoter DNA methylation was not related to this finding, suggesting there are other mechanisms involved in transcriptional control.