Epstein-Barr Virus Mediated Signaling in Nasopharyngeal Carcinoma Carcinogenesis.
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ABSTRACT:
SUBMITTER: Richardo T
PROVIDER: S-EPMC7565514 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
Publications
Epstein-Barr Virus Mediated Signaling in Nasopharyngeal Carcinoma Carcinogenesis.
Richardo Timmy T Prattapong Pongphol P Ngernsombat Chawalit C Wisetyaningsih Nurulfitri N Iizasa Hisashi H Yoshiyama Hironori H Janvilisri Tavan T
Cancers 20200828 9
Nasopharyngeal carcinoma (NPC) is one of the most common tumors occurring in China and Southeast Asia. Etiology of NPC seems to be complex and involves many determinants, one of which is Epstein-Barr virus (EBV) infection. Although evidence demonstrates that EBV infection plays a key role in NPC carcinogenesis, the exact relationship between EBV and dysregulation of signaling pathways in NPC needs to be clarified. This review focuses on the interplay between EBV and NPC cells and the correspondi ...[more]
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Project description:Nasopharyngeal carcinoma (NPC) is consistently associated with Epstein-Barr virus (EBV) infection in regions in which it is endemic, including Southern China and Southeast Asia. The high mortality rates of NPC patients with advanced and recurrent disease highlight the urgent need for effective treatments. While recent genomic studies have revealed few druggable targets, the unique interaction between the EBV infection and host cells in NPC strongly implies that targeting EBV may be an efficient approach to cure this virus-associated cancer. Key features of EBV-associated NPC are the persistence of an episomal EBV genome and the requirement for multiple viral latent gene products to enable malignant transformation. Many translational studies have been conducted to exploit these unique features to develop pharmaceutical agents and therapeutic strategies that target EBV latent proteins and induce lytic reactivation in NPC. In particular, inhibitors of the EBV latent protein EBNA1 have been intensively explored, because of this protein's essential roles in maintaining EBV latency and viral genome replication in NPC cells. In addition, recent advances in chemical bioengineering are driving the development of therapeutic agents targeting the critical functional regions of EBNA1. Promising therapeutic effects of the resulting EBNA1-specific inhibitors have been shown in EBV-positive NPC tumors. The efficacy of multiple classes of EBV lytic inducers for NPC cytolytic therapy has also been long investigated. However, the lytic-induction efficiency of these compounds varies among different EBV-positive NPC models in a cell-context-dependent manner. In each tumor, NPC cells can evolve and acquire somatic changes to maintain EBV latency during cancer progression. Unfortunately, the poor understanding of the cellular mechanisms regulating EBV latency-to-lytic switching in NPC cells limits the clinical application of EBV cytolytic treatment. In this review, we discuss the potential approaches for improvement of the above-mentioned EBV-targeting strategies.
| S-EPMC7247807 | biostudies-literature
Project description:Nasopharyngeal carcinoma (NPC) is a metastasis-prone malignancy closely associated with the Epstein-Barr virus (EBV). Despite ubiquitous infection of EBV worldwide, NPC incidences displayed predominance in certain ethnic groups and endemic regions. The majority of NPC patients are diagnosed with advanced-stage disease, as a result of anatomical isolation and non-specific clinical manifestation. Over the decades, researchers have gained insights into the molecular mechanisms underlying NPC pathogenesis as a result of the interplay of EBV infection with several environmental and genetic factors. EBV-associated biomarkers were also used for mass population screening for the early detection of NPC. EBV and its encoded products also serve as potential targets for the development of therapeutic strategies and tumour-specific drug delivery. This review will discuss the pathogenic role of EBV in NPC and efforts in exploiting the potential of EBV-associated molecules as biomarkers and therapeutic targets. The current knowledge on the role of EBV and its associated products in NPC tumorigenesis, development and progression will offer a new outlook and potential intervention strategy against this EBV-associated malignancy.
| S-EPMC9947861 | biostudies-literature
Project description:Our goal in this work was to illustrate the Epstein-Barr virus (EBV)-modulated global biochemical profile and provide a novel metabolism-related target to improve the therapeutic regimen of nasopharyngeal carcinoma (NPC). We used a metabolomics approach to investigate EBV-modulated metabolic changes, and found that the exogenous overexpression of the EBV-encoded latent membrane protein 1 (LMP1) significantly increased glycolysis. The deregulation of several glycolytic genes, including hexokinase 2 (HK2), was determined to be responsible for the reprogramming of LMP1-mediated glucose metabolism in NPC cells. The upregulation of HK2 elevated aerobic glycolysis and facilitated proliferation by blocking apoptosis. More importantly, HK2 was positively correlated with LMP1 in NPC biopsies, and high HK2 levels were significantly associated with poor overall survival of NPC patients following radiation therapy. Knockdown of HK2 effectively enhanced the sensitivity of LMP1-overexpressing NPC cells to irradiation. Finally, c-Myc was demonstrated to be required for LMP1-induced upregulation of HK2. The LMP1-mediated attenuation of the PI3-K/Akt-GSK3beta-FBW7 signaling axis resulted in the stabilization of c-Myc. These findings indicate a close relationship between EBV and glycolysis in NPC. Notably, LMP1 is the key regulator of the reprogramming of EBV-mediated glycolysis in NPC cells. Given the importance of EBV-mediated deregulation of glycolysis, anti-glycolytic therapy might represent a worthwhile avenue of exploration in the treatment of EBV-related cancers.
| S-EPMC4162460 | biostudies-literature
Project description:Epstein-Barr Virus (EBV) establishes a long-term latent infection and is associated with a number of human malignancies that are thought to arise from deregulation of different stages of the viral life cycle. Recently, a large number of microRNAs (miRNAs) have been described for EBV, and it has been suggested that their expression may vary between the different latency states found in normal and malignant tissue. To date, however, no technique has been utilized to comprehensively and quantitatively test this idea by profiling expression of the EBV miRNAs in primary infected tissues. We describe here a multiplex reverse transcription-PCR assay that allows the profiling of 39 of the 40 known mature EBV miRNAs from as little as 250 ng of RNA. With this approach, we present a comprehensive profile of EBV miRNAs in primary nasopharyngeal carcinoma (NPC) tumors including estimates of miRNA copy number per tumor cell. This is the first comprehensive profiling of EBV miRNAs in any EBV-associated tumor. In contrast to previous suggestions, we show that the BART-derived miRNAs are present in a wide range of copy numbers from < or =10(3) per cell in both primary tumors and the widely used NPC-derived C666-1 cell line. However, we confirm the hypothesis that the BHRF1 miRNAs are not expressed in NPC. Lastly, we demonstrate that EBV miRNA expression in the widely used NPC line C666-1 is, with some caveats, broadly representative of primary NPC tumors.
| S-EPMC2643705 | biostudies-literature
Project description:AIM:In recent years, studies have suggested that Epstein-Barr virus (EBV) is associated with HCC. The present study was to determine the prevalence of EBV in HCC patients, and whether EBV acted synergistically with hepatitis viruses in HCC carcinogenesis. METHODS:Liver tissue 115 HCC patients and 26 non-carcinoma patients were studied. Polymerase chain reaction (PCR) was performed to detect EBV BamHI W DNA, EBV LMP1 DNA, HBV X DNA, and HBV S DNA. Reverse transcription PCR (RT-PCR) was performed to detect HCV RNA and HDV RNA. Immunohistochemistry was performed to detect LMP1, HBsAg, HBcAg and HCV. The positive ratios were compared between HCC group and control group by chi2 test. RESULTS:Totally, 78 HCC samples whose beta-globulin DNA was positively detected by amplified PCR were selected. PCR was performed in all cases for EBV DNA and HBV DNA. RT-PCR was performed in 18 cases for HCV RNA and HDV RNA. EBV BamHI W and EBV LMP1 were positive in 18 and 6 cases, respectively. HBV X gene and HBV S gene were positive in 42 and 27 cases respectively. HCV was positive in one of the 18 cases, and none was positive for HDV. The positive rates were 28.2% (22 of 78) for EBV DNA (BamHI W and/or LMP1) and 56.4% (44 of 78) for HBV DNA (X gene and/or S gene) respectively. In addition, 12 cases were positive for both EBV DNA and HBV DNA. Among the 26 cases in the control group, 2 cases were positive for EBV BamHI W, 4 positive for HBV X gene and 3 positive for HBV S gene. The positive rates were 8.0% (2 of 26) and 23.1% (6 of 26), respectively, for EBV DNA and HBV DNA. The result of DNA sequencing of BamHI W was 100% homologous with the corresponding sequence of B95-8. There was significant difference in EBV infection rate between HCC patients and controls (chi2 = 4.622, P<0.05). The difference in HBV infection rate was also significant (chi2 = 8.681, P<0.05). However, there was no obvious correlation between HBV and EBV in HCC patients (chi2 = 0.835, P>0.05). LMP1, HBV (HBsAg, HBcAg) and HCV were detected positively in 25, 45 and 6 of 78 cases of HCC tissues respectively. In the 26 control cases, the corresponding positive cases were 2, 4 and 0. The difference in EBV infection rate between HCC patients and control cases was statistically significant (chi2 = 6.02, P<0.05). The difference in HBV infection rate was also statistically significant (chi2 = 10.03, P<0.05). In the 25 cases with positive LMP1 expression, 6 were in the nuclei of tumor cells, 9 in the cytoplasm of tumor cells and 10 in mesenchymal lymphocyte cytoplasm. CONCLUSION:The existence of EBV infection in HCC tissues suggests that EBV may be involved in the hepatocellular carcinogenesis in China. HBV infection may be a major cause of HCC. There is no correlation between EBV and HBV in the development of HCC. The prevalence of HCV infection is low in our area, and HDV appears not to play a direct role in hepatocellular carcinogenesis.
| S-EPMC4576219 | biostudies-literature
Project description:Epstein-Barr virus (EBV) promotes tumor angiogenesis in nasopharyngeal carcinoma (NPC) by activating store-operated Ca2+ entry. Since such entry has been linked to stromal interaction molecule 1 (STIM1), we examined whether the virus acts via STIM1-dependent Ca2+ signaling to promote tumor angiogenesis in NPC. STIM1 expression was detected in NPC cell lines HK1 and CNE2 that were negative or positive for EBV. STIM1 was knocked down in EBV-positive cells using recombinant lentivirus, then cytosolic Ca2+ levels were measured based on fluorescence resonance energy transfer. Cells were also exposed to epidermal growth factor (EGF), and secretion of vascular endothelial growth factor (VEGF) was measured using an enzyme-linked immunosorbent assay. Endothelial tube formation was quantified in an in vitro angiogenesis assay. Growth of CNE2-EBV xenografts was measured in mice, and angiogenesis was assessed based on immunohistochemical staining against CD31. Paraffin-embedded NPC tissues from patients were assayed for CD31 and STIM1. EGFR and ERK signaling pathways were assessed in NPC cell lines. STIM1 expression was higher in EBV-positive than in EBV-negative NPC cell lines. STIM1 knockdown in EBV-positive NPC cells significantly reduced Ca2+ influx and VEGF production after EGF treatment. STIM1 knockdown also inhibited xenograft growth and angiogenesis. Moreover, CD31 expression level was higher in EBV-positive than EBV-negative NPC tissues, and high expression of CD31 co-localized with high expression of STIM1 in EBV-positive tissues from NPC patients. Viral infection of NPC cells led to higher levels of phosphorylated ERK1/2 after EGF treatment, which STIM1 knockdown partially reversed. Our results suggest that EBV promotes EGF-induced ERK1/2 signaling by activating STIM1-dependent Ca2+ signaling, and that blocking such signaling may inhibit EBV-promoted angiogenesis in NPC.
| S-EPMC8537240 | biostudies-literature
Project description:Epstein-Barr virus (EBV) is the prototypical example for episomal persistence of genetic information. Yet, little is known about how this viral episome is lost. Episome loss occurs naturally in nasopharyngeal carcinoma (NPC) upon explantation into culture. Using whole-genome profiling, we found evidence for 2 different pathways of episome loss: (i) rapid loss of the entire episome or (ii) successive mutation/deletion of the episome until at least 1 essential cis-element is destroyed. This second phenotype was seen in a clone of HONE-1 NPC cells that maintains the EBV episome for prolonged time in culture. The conceptual insights provided by our quantitative analysis should aid our understanding of mammalian episomes, as well as lead to designs to cure latent viral infection.
| S-EPMC2866115 | biostudies-literature
Project description:Nasopharyngeal carcinoma (NPC) is the most common cancer originating from the nasopharynx, and can be induced by infection with Epstein-Barr virus (EBV). To study the mechanisms of EBV-associated NPC, a microarray of the GSE12452 dataset was analyzed. GSE12452 was downloaded from Gene Expression Omnibus and consisted of 31 NPC samples and 10 normal healthy nasopharyngeal tissue samples. The differentially-expressed genes (DEGs) were screened using the linear models for microarray data package in R. Using Database for Annotation, Visualization and Integrated Discovery software, potential functions of the DEGs were predicted by Gene Ontology and pathway enrichment analyses. With the information from the Search Tool for the Retrieval of Interacting Genes/Proteins database, the protein-protein interaction (PPI) network was visualized by Cytoscape. Furthermore, modules of the PPI network were searched using ClusterONE in Cytoscape. A total of 951 DEGs were screened in the NPC samples compared with the normal healthy nasopharyngeal tissue samples. Function enrichment indicated that the upregulated genes were associated with the cell cycle, cytoskeleton organization and DNA metabolism. Meanwhile, the downregulated genes were mainly associated with cell differentiation, hormone metabolism, inflammatory response and immune response. PPI networks for the DEGs suggested that upregulated mitotic arrest deficient 2-like 1 (MAD2L1; degree=133), proliferating cell nuclear antigen (PCNA; degree=125) and cyclin B1 (CCNB1; degree=115), and downregulated member A1 of aldehyde dehydrogenase 1 (ALDH1A1; degree=15) may be of great importance as they exhibited higher degrees on interaction. Mucin 1 (MUC1) was a key node of module 4. Overall, the study indicated that MAD2L1, CCNB1, PCNA, ALDH1A1 and MUC1 may have a correlation with EBV-associated NPC.
| S-EPMC5038861 | biostudies-literature
Project description:Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated malignancy. The principal oncogene of EBV, latent membrane protein 1 (LMP1), induces the expression of programmed death-ligand 1 (PD-L1), which is an immunosuppressive transmembrane protein and a promising therapeutic target for various malignancies. Recent studies have revealed an association between the level of soluble PD-L1 (sPD-L1) and disease progression. However, the role of sPD-L1 in NPC or its relevance to LMP1 has not been elucidated. This study aimed to examine whether LMP1 induces sPD-L1 in vitro and analyze the clinical relevance of LMP1, PD-L1, and sPD-L1 in NPC patients. Analysis of nasopharyngeal cell lines revealed that LMP1 induces both cellular PD-L1 and sPD-L1. Analysis of biopsy specimens from 32 NPC patients revealed that LMP1 expression was significantly correlated with PD-L1 expression. Finally, the serum sPD-L1 level in NPC patients was higher than that in the controls. Moreover, the sPD-L1 level in the advanced stage was higher than that in the early stage. However, LMP1 expression, PD-L1 expression, and sPD-L1 levels were not associated with prognosis. These results suggest that LMP1 induces both sPD-L1 and PD-L1, which are associated with NPC progression.
| S-EPMC7998736 | biostudies-literature
Project description:Non-coding RNAs have been shown to play important regulatory roles, notably in cancer development. In this study, we investigated the role of microRNAs and circular RNAs in Nasopharyngeal Carcinoma (NPC) by constructing a circRNA-miRNA-mRNA co-expression network and performing differential expression analysis on mRNAs, miRNAs, and circRNAs. Specifically, the Epstein-Barr virus (EBV) infection has been found to be an important risk factor for NPC, and potential pathological differences may exist for EBV+ and EBV- subtypes of NPC. By comparing the expression profile of non-cancerous immortalized nasopharyngeal epithelial cell line and NPC cell lines, we identified differentially expressed coding and non-coding RNAs across three groups of comparison: cancer vs. non-cancer, EBV+ vs. EBV- NPC, and metastatic vs. non-metastatic NPC. We constructed a ceRNA network composed of mRNAs, miRNAs, and circRNAs, leveraging co-expression and miRNA target prediction tools. Within the network, we identified the regulatory ceRNAs of CDKN1B, ZNF302, ZNF268, and RPGR. These differentially expressed axis, along with other miRNA-circRNA pairs we identified through our analysis, helps elucidate the genetic and epigenetic changes central to NPC progression, and the differences between EBV+ and EBV- NPC.
| S-EPMC8600047 | biostudies-literature