TLR9 Polymorphisms Might Contribute to the Ethnicity Bias for EBV-Infected Nasopharyngeal Carcinoma.
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ABSTRACT:
SUBMITTER: Roy Chattopadhyay N
PROVIDER: S-EPMC7068130 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Epstein-Barr virus (EBV) was the first tumor virus in humans. Nasopharyngeal carcinoma (NPC) accounts for approximately 60% of the 200,000 new tumor cases caused by EBV infection worldwide each year. NPC has an insidious onset and is highly malignant, with more than 70% of patients having intermediate to advanced disease at the time of initial diagnosis, and is strongly implicated in epithelial cancers as well as malignant lymphoid and natural killer/T cell lymphomas. Over 90% of patients with confirmed undifferentiated NPC are infected with EBV. In recent decades, much progress has been made in understanding the molecular mechanisms of NPC and developing therapeutic approaches. Radiotherapy and chemotherapy are the main treatment options for NPC; however, they have a limited efficacy in patients with locally advanced or distant metastatic tumors. Tumor immunotherapy, including vaccination, adoptive cell therapy, and immune checkpoint blockade, represents a promising therapeutic approach for NPC. Significant breakthroughs have recently been made in the application of immunotherapy for patients with recurrent or metastatic NPC (RM-NPC), indicating a broad prospect for NPC immunotherapy. Here, we review important research findings regarding immunotherapy for NPC patients and provide insights for future research.
| S-EPMC9875085 | biostudies-literature
Project description:Nasopharyngeal carcinoma (NPC) is a rare cancer of the nasopharyngeal mucosa with a specific geographic predisposition. NPC is often associated with Epstein-Barr Virus (EBV) infection and as a result contains many characteristic biomarkers. Treatment of locally-contained NPC is generally achieved through use of radiotherapy (RT), as part of a multimodality treatment regimen. Induction chemotherapy followed by concurrent RT and platinum-based chemotherapy regimen has emerged as the definitive treatment of choice for locoregionally-advanced NPC. Recently, immunotherapy is finding a role in the treatment of recurrent or metastatic NPC. Immune checkpoint blockade therapies targeted against the programmed death-1 (PD-1) receptor have demonstrated efficacy in early phase clinical trials, with ongoing phase III trials in effect. Biomarkers for treatment efficacy remain an ongoing area of investigation, with important prognostic implications on the horizon.
| S-EPMC8657235 | biostudies-literature
Project description:BackgroundNasopharyngeal carcinoma (NPC) is mainly concentrated in East and Southeast Asia. This study aims to elucidate the potential associations of functional SNPs in the fat mass and obesity associated gene (FTO) with NPC risk and radiotherapy outcomes in a Chinese population.MethodsFunctional SNP rs1477196 G>A, rs9939609 T>A, rs7206790 C>G, and rs8047395 A>G were genotyped and evaluated for their associations with NPC risk and radiotherapy outcomes.ResultsBoth rs9939609 (allele A versus allele T: OR=1.59; 95% CI=1.17-2.17; P-value=0.003) and rs8047395 (allele G versus allele A: OR=0.76; 95% CI=0.64-0.9; P-value=0.002) were significantly associated with risk of NPC. GTEx showed risk allele A of rs9939609 and rs8047395 were significantly associated with higher FTO mRNA levels in skeletal muscle tissue, which also corroborated our findings. Meanwhile, both rs1477196 (allele A versus allele G: OR=1.64; 95% CI=1.09-2.49; P-value=0.019) and rs9939609 (allele A versus allele T: OR=0.61; 95% CI=0.43-0.87; P-value=0.006) were significantly associated with complete remission (CR) of NPC.ConclusionOur study identified that FTO polymorphisms contributed to the susceptibility and radiotherapy efficacy of NPC. These results shed light on the potential of establishing markers for predicting risk and personalized treatment of NPC.
| S-EPMC8487284 | biostudies-literature
Project description:Nasopharyngeal carcinoma (NPC) is a disease that is closely associated with EBV infection. Toll-like receptor 9 is an important factor mediating the interaction between EBV and the host immune response. Any genetic (single nucleotide polymorphisms, SNPs) or expression variation in TLR9 gene may modify the ability of the receptor to respond correctly to viral infection as in NPC. This study is aimed at evaluating the effect of TLR9 functional polymorphisms (TLR9-1486 T/C and TLR9-1237 T/C) and TLR9 mRNA expression in NPC severity and progression at diagnosis and after treatment. This study included 322 patients with NPC. RFLP-PCR and real-time PCR were used to assess, respectively, the genotypes and the mRNA expression of TLR9 gene. The genotyping analysis showed that the presence of mutated allele -1237C (TLR9-1237 TC+CC) was associated with large tumor size (p = 0.017; OR (CI?95%) = 1.888 (1.11-3.19)) at diagnosis. After treatment, the -1237C allele was associated with a better chance of complete remission (p = 0.031, OR (CI?95%) = 0.486 (0.25-0.95)), a lower risk of distant metastasis (p = 0.028, OR (CI?95%) = 0.435 (0.18-1.02)), and a lower risk of death by NPC (p = 0.003, OR (CI?95%) = 0.20 (0.06-0.67)). Kaplan-Meier analysis showed that patients with -1237CC and -1237TC genotypes had a better overall survival (OVS) (p < 0.01) and distant metastasis-free survival (DMFS) (p < 0.05). A multivariate analysis revealed that TLR9-1237 T/C polymorphism was an independent prognostic factor in OVS (p = 0.02; HR = 0.244) and DMFS (p = 0.048; HR = 0.388). The transcriptomic analysis showed that the mRNA expression was reduced in patients with larger tumor size (T4) (p = 0.013) and advanced clinical stage (SIII-SIV) (p = 0.037). The TLR9 mRNA expression was inversely correlated with tumor size (p = 0.014; r = -0.314) at diagnosis. Our results indicated for the first time that the functional -1237 T/C polymorphism and mRNA expression of TLR9 gene may be considered as protective factors for NPC severity and progression.
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Project description:Nasopharyngeal carcinoma (NPC) is a unique EBV-associated epithelial malignancy, showing highly invasive and metastatic phenotype. Despite increasing evidence demonstrating the critical role of cancer stem-like cells (CSCs) in the maintenance and progression of tumors in a variety of malignancies, the existence and properties of CSC in EBV-associated NPC are largely unknown. Our study aims to elucidate the presence and role of CSCs in the pathogenesis of this malignant disease. Sphere-forming cells were isolated from an EBV-positive NPC cell line C666-1 and its tumor-initiating properties were confirmed by in vitro and in vivo assays. In these spheroids, up-regulation of multiple stem cell markers were found. By flow cytometry, we demonstrated that both CD44 and SOX2 were overexpressed in a majority of sphere-forming C666-1 cells. The CD44+SOX2+ cells was detected in a minor population in EBV-positive xenografts and primary tumors and considered as potential CSC in NPC. Notably, the isolated CD44+ NPC cells were resistant to chemotherapeutic agents and with higher spheroid formation efficiency, showing CSC properties. On the other hand, microarray analysis has revealed a number of differentially expressed genes involved in transcription regulation (e.g. FOXN4, GLI1), immune response (CCR7, IL8) and transmembrane transport (e.g. ABCC3, ABCC11) in the spheroids. Among these genes, increased expression of CCR7 in CD44+ CSCs was confirmed in NPC xenografts and primary tumors. Importantly, blocking of CCR7 abolished the sphere-forming ability of C666-1 in vitro. Expression of CCR7 was associated with recurrent disease and distant metastasis. The current study defined the specific properties of a CSC subpopulation in EBV-associated NPC. Our findings provided new insights into developing effective therapies targeting on CSCs, thereby potentiating treatment efficacy for NPC patients.
| S-EPMC3528656 | biostudies-literature
Project description:Pathogen-induced inflammation has been one of the intensive research areas in carcinogenesis. EBV encoded RNAs (EBERs) have been suggested to play roles in anti-apoptosis and growth-promotion in lymphoid and immune disorders. However, pathological roles of EBERs in solid tumors of epithelia origin remain to be elucidated. Given their characteristic dsRNA structures, recent studies provided evidences for the activation of some pattern recognition receptors (PRR) by EBERs, which is fundamental in the process of pathogenesis. Here, we show that EBERs induce inflammatory response in nasopharyngeal carcinoma (NPC) cells through Toll-like receptor 3 (TLR3), mainly featured by high level of TNFα production. Interestingly, EBERs and EBV latent membrane protein 1 (LMP1) form a positive regulatory loop with NF-κB as a key node that amplifies the inflammatory signals in EBV infected epithelial cells. We demonstrate in vivo that EBERs can interact with TLR3 and induce tumor cells to produce cytokines in B16 synergetic tumor and human NPC xenograft models, in which macrophages are recruited and activated, leading to a favorable microenvironment for solid tumor growth. Lastly, we verify a positive association between EBER and TNFα levels in NPC clinical samples and the combination of EBER and TNFα expressions provides a predictor of poor survival of NPC patients. In conclusion, EBERs play a pivotal role in inflammation-to-oncogenesis transition in NPC development.
| S-EPMC4695186 | biostudies-literature
Project description:Nasopharyngeal carcinoma (NPC) is a highly invasive epithelial malignancy that is prevalent in southern China and Southeast Asia. It is consistently associated with latent Epstein-Barr virus (EBV) infection. In NPC, miR-BARTs, the EBV-encoded miRNAs derived from BamH1-A rightward transcripts, are abundantly expressed and contribute to cancer development by targeting various cellular and viral genes. In this study, we establish a comprehensive transcriptional profile of EBV-encoded miRNAs in a panel of NPC patient-derived xenografts and an EBV-positive NPC cell line by small RNA sequencing. Among the 40 miR-BARTs, predominant expression of 22 miRNAs was consistently detected in these tumors. Among the abundantly expressed EBV-miRNAs, BART5-5p, BART7-3p, BART9-3p, and BART14-3p could negatively regulate the expression of a key DNA double-strand break (DSB) repair gene, ataxia telangiectasia mutated (ATM), by binding to multiple sites on its 3'-UTR. Notably, the expression of these four miR-BARTs represented more than 10% of all EBV-encoded miRNAs in tumor cells, while downregulation of ATM expression was commonly detected in all of our tested sequenced samples. In addition, downregulation of ATM was also observed in primary NPC tissues in both qRT-PCR (16 NP and 45 NPC cases) and immunohistochemical staining (35 NP and 46 NPC cases) analysis. Modulation of ATM expression by BART5-5p, BART7-3p, BART9-3p, and BART14-3p was demonstrated in the transient transfection assays. These findings suggest that EBV uses miRNA machinery as a key mechanism to control the ATM signaling pathway in NPC cells. By suppressing these endogenous miR-BARTs in EBV-positive NPC cells, we further demonstrated the novel function of miR-BARTs in inhibiting Zta-induced lytic reactivation. These findings imply that the four viral miRNAs work co-operatively to modulate ATM activity in response to DNA damage and to maintain viral latency, contributing to the tumorigenesis of NPC. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
| S-EPMC5888186 | biostudies-literature
Project description:Nasopharyngeal carcinoma (NPC) is a highly metastatic cancer that is consistently associated with Epstein-Barr virus (EBV) infection. In this study, we identify for the first time a role for monoamine oxidase A (MAOA) in NPC. MAOA is a mitochondrial enzyme that catalyzes oxidative deamination of neurotransmitters and dietary amines. Depending on the cancer type, MAOA can either have a tumour-promoting or tumour-suppressive role. We show that MAOA is down-regulated in primary NPC tissues and its down-regulation enhances the migration of NPC cells. In addition, we found that EBV infection can down-regulate MAOA expression in both pre-malignant and malignant nasopharyngeal epithelial (NPE) cells. We further demonstrate that MAOA is down-regulated as a result of IL-6/IL-6R/STAT3 signalling and epigenetic mechanisms, effects that might be attributed to EBV infection in NPE cells. Taken together, our data point to a central role for EBV in mediating the tumour suppressive effects of MAOA and that loss of MAOA could be an important step in the pathogenesis of NPC.
| S-EPMC7145851 | biostudies-literature
Project description:Epstein-Barr virus (EBV) infection is a major etiological factor for nasopharyngeal carcinoma (NPC). Several EBV-encoded BART miRNAs have been associated with viral latency, immune escape, cell survival, cell proliferation and apoptosis. Here, we report that EBV-miR-BART7-3p, an EBV-encoded BART miRNA highly expressed in NPC, was correlated with cell-cycle progression in vitro and increased tumor formation in vivo. This viral miRNA stimulated the PTEN/PI3K/Akt pathway and induced c-Myc and c-Jun. Knockdown of PTEN mimicked EBV-miR-BART7-3p-induced tumorigenic phenotype. Based on these results, we conducted a therapeutic experiment by using gold nano-particles (AuNPs) carrying anti-EBV-miR-BART7-3p. Silencing of EBV-miR-BART7-3p reduced tumor growth in animal model. We conclude that EBV-miR-BART7-3p favors carcinogenesis, representing a potential target for miRNA-based therapy.
| S-EPMC4480720 | biostudies-literature
Project description:BackgroundNumerous individual studies have investigated the diagnostic value of EBV-DNA, EA-IgA, VCA-IgA, EBNA1-IgA and Rta-IgG detection for nasopharyngeal carcinoma (NPC), but the conclusions remain controversial. This meta-analysis aimed to determine the value of EBV-DNA, EA-IgA, VCA-IgA, EBNA1-IgA and Rta-IgG detection in the diagnosis of NPC.MethodsPROSPERO registration number: CRD42019145532. PubMed, EMBASE, Cochrane Library, and Chinese data libraries (Wanfang, CNKI, and CBM) were searched up to January 2019. The pooled sensitivity, specificity, and positive likelihood, negative likelihood, and diagnostic odds ratios were conducted in this meta-analysis. Summary receiver operating characteristic curves evaluated the test-performance global summary. Publication bias was examined by Deek's funnel plot asymmetry test.ResultsForty-seven studies with 8382 NPC patients (NPC group) and 15,089 individuals without NPC (Control group) were included in this meta-analysis. The sensitivity, specificity, positive likelihood (+ LR), negative likelihood (-LR), DOR and AUC of EBV-DNA in diagnosis of NPC were: 0.76 (95% CI 0.73-0.77), 0.96 (95% CI 0.95-0.97), 14.66 (95% CI 9.97-21.55), 0.19 (95% CI 0.13-0.28), 84 (95% CI 50.45-139.88), 0.96 (SE: 0.001), and 0.55 (95% CI 0.54-0.57), 0.96 (95% CI 0.96-0.97), 12.91 (95% CI 9.55-17.45), 0.35 (95% CI 0.29-0.43), 39.57 (95% CI 26.44-59.23), 0.94 (SE: 0.002) for the EA-IgA, and 0.85 (95% CI 0.84-0.85), 0.89 (95% CI 0.88-0.89), 6.73 (95% CI5.38-8.43), 0.17 (95% CI 0.12-0.23), 43.03 (95% CI 31.51-58.76), 0.93 (SE: 0.007) for the VCA-IgA, and 0.86 (95% CI 0.85-0.88), 0.87 (95% CI 0.88-0.90), 7.55 (95% CI 5.79-9.87), 0.16 (95% CI 0.13-0.19), 50.95 (95% CI 34.35-75.57), 0.94 (SE: 0.008) for the EBNA1-IgA, and 0.70 (95% CI 0.69-0.71), 0.94 (95% CI 0.94-0.95), 9.84 (95% CI 8.40-11.54), 0.25 (95% CI 0.21-0.31), 40.59 (95% CI 32.09-51.35), 0.95 (SE: 0.005) for the Rta-IgG. The EBV-DNA had larger AUC compared with other EBV-based antibodies (P < 0.05), while the difference between EA-IgA, VCA-IgA, EBNA1-IgA and Rta-IgG was not statistically significant (P > 0.05).ConclusionsEBV-DNA, VCA-IgA, EBNA1-IgA and Rta-IgG detection have high accuracy in early diagnosis NPC. In addition, EBV-DNA detection has the higher diagnosis accuracy in NPC. On the other hand, EA-IgA is suitable for the diagnosis but not NPC screening.
| S-EPMC7944913 | biostudies-literature