Epstein-Barr Virus Infection Alone or Jointly with Human Papillomavirus Associates with Down-Regulation of miR-145 in Oral Squamous-Cell Carcinoma.
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ABSTRACT:
SUBMITTER: Heawchaiyaphum C
PROVIDER: S-EPMC8708579 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The Epstein-Barr virus (EBV) is a human herpesvirus associated with various cancers. The number of reports that describe infection of EBV in oral squamous carcinoma cells is increasing. However, there is no available in vitro model to study the possible role of EBV in the development of oral squamous cell carcinoma. Herein, we report establishment of a latent EBV infection of well-differentiated HSC1 cells and poorly differentiated SCC25 cells. Viral copy numbers per cell in EBV-infected HSC1 and SCC25 cells are 2 and 5, respectively. Although the EBV copy number was small, spontaneous viral replication was observed in EBV-infected HSC1 cells. Contrarily, infectious viral production was not observed in EBV-infected SCC25 cells, despite containing larger number of EBV genomes. Chemical activation of cells induced expression of viral lytic BZLF1 gene in EBV-infected HSC1 cells, but not in EBV-infected SCC25 cells. EBV infection activated proliferation and migration of HSC1 cells. However, EBV-infection activated migration but not proliferation in SCC25 cells. In conclusion, EBV can infect squamous cells and establish latent infection, but promotion of cell proliferation and of lytic EBV replication may vary depending on stages of cell differentiation. Our model can be used to study the role of EBV in the development of EBV-associated oral squamous cell carcinoma.
| S-EPMC7144007 | biostudies-literature
Project description:BackgroundThe evidence for association between Epstein-Barr virus (EBV) infection and risk of oral squamous cell carcinoma (OSCC) is inconsistent in the literature. Therefore, this meta-analysis was conducted to clarify this association.MethodsA literature search was conducted in electronic databases for English- and Chinese-language publications until March 31, 2017 to include eligible case-control studies. The pooled odds ratio (OR) and 95% confidence interval (95% CI) were estimated to determine the association between EBV infection and OSCC risk using a fixed- or random-effects model based on heterogeneity. Publication bias was assessed using funnel plot analysis.ResultsA total of 13 case-control studies with 686 OSCC patients and 433 controls were included based on predetermined inclusion and exclusion criteria. The pooled OR with 95% CI between EBV infection and OSCC risk was 5.03 (1.80-14.01) with significant heterogeneity observed (I2 = 87%). The subgroup analysis indicates that the year of publication, study location, economic level, sample size, tissue type, detection method and marker, control type, and language might explain potential sources of heterogeneity. Publication bias was not observed, and sensitivity analysis showed stable results.ConclusionsThe results of the current meta-analysis suggest that EBV infection is statistically associated with increased risk of OSCC. However, additional high-quality studies with larger sample sizes are needed to further confirm the relationship between EBV and OSCC.
| S-EPMC5655447 | biostudies-literature
Project description:The DOK1 tumor suppressor gene encodes an adapter protein that acts as a negative regulator of several signaling pathways. We have previously reported that DOK1 expression is up-regulated upon cellular stress, via the transcription factor E2F1, and down-regulated in a variety of human malignancies due to aberrant hypermethylation of its promoter. Here we show that Epstein Barr virus (EBV) infection of primary human B-cells leads to the down-regulation of DOK1 gene expression via the viral oncoprotein LMP1. LMP1 alone induces recruitment to the DOK1 promoter of at least two independent inhibitory complexes, one containing E2F1/pRB/DNMT1 and another containing at least EZH2. These events result in tri-methylation of histone H3 at lysine 27 (H3K27me3) of the DOK1 promoter and gene expression silencing. We also present evidence that the presence of additional EBV proteins leads to further repression of DOK1 expression with an additional mechanism. Indeed, EBV infection of B-cells induces DNA methylation at the DOK1 promoter region including the E2F1 responsive elements that, in turn, lose the ability to interact with E2F complexes. Treatment of EBV-infected B-cell-lines with the methyl-transferase inhibitor 5-aza-2'-deoxycytidine rescues DOK1 expression. In summary, our data show the deregulation of DOK1 gene expression by EBV and provide novel insights into the regulation of the DOK1 tumor suppressor in viral-related carcinogenesis.
| S-EPMC4014463 | biostudies-literature
Project description:BackgroundEpstein-Barr Virus (EBV) is a human oncogenic virus that can lead to cancer in lymphoid and epithelial cells and is one of the hypothesized causes of oral cavity lesions including oral squamous cell carcinoma (OSCC), but the etiological association remains undetermined. The present investigation aimed to explore the EBV presence, viral load, and EBV-encoded small RNA (EBER) sequence variation in tissue samples of patients with OSCC and other oral cavity lesions including oral lichen planus (OLP), and oral irritation fibroma (OIF).MethodsIn total, 88 oral cavity samples (23 with OSCC, 29 with OLP, and 36 with OIF diagnosis) were examined by Real-Time PCR technique and some of them were sequenced.ResultsViral EBER sequence was detected in 6 out of the 23 OSCC (31.4%), 6 out of the 29 OLP (20.7%), and 3 out of the 36 OIF cases (8.3%). The mean EBV copy number was higher in OSCC samples (1.2 × 10-2 ± 1.3 × 10-2 copies/cell) compared to OLP (2.2 × 10-3 ± 2.6 × 10-3 copies/cell) and OIF (2.4 × 10-4 ± 2.0 × 10-4 copies/cell) samples, although this difference was not statistically significant (P = 0.318). The EBER gene was amplified and sequenced in 5 OSCC, 3 OLP, and 2 OIF samples with high EBV viral load. One OSCC, two OLP, and two OIF isolates showed different nucleotide variations compared with EBV-WT and AG876 prototype sequences: C6834T, C6870T, C6981T, C7085T, C7085G, and C7094T.ConclusionIn our study the presence of more than one genome copies per tumor cell indicates the possible role of EBV infection in oral cancers. However, more studies should be conducted to clarify the role of EBV in OSCC carcinogenesis.
| S-EPMC8495909 | biostudies-literature
Project description:Epstein-Barr virus (EBV) is implicated in the pathogenesis of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OSCC). EBV-associated cancers harbor a latent EBV infection characterized by a lack of viral replication and the expression of viral oncogenes. Cellular changes promoted by HPV are comparable to those shown to facilitate EBV latency, though whether HPV-positive cells support a latent EBV infection has not been demonstrated. Using a model of direct EBV infection into HPV16-immortalized tonsillar cells grown in organotypic raft culture, we showed robust EBV replication in HPV-negative rafts but little to no replication in HPV-immortalized rafts. The reduced EBV replication was independent of immortalization, as human telomerase-immortalized normal oral keratinocytes supported robust EBV replication. Furthermore, we observed reduced EBV lytic gene expression and increased expression of EBER1, a noncoding RNA highly expressed in latently infected cells, in the presence of HPV. The use of human foreskin keratinocyte rafts expressing the HPV16 E6 and/or E7 oncogene(s) (HPV E6 and E7 rafts) showed that E7 was sufficient to reduce EBV replication. EBV replication is dependent upon epithelial differentiation and the differentiation-dependent expression of the transcription factors KLF4 and PRDM1. While KLF4 and PRDM1 levels were unaltered, the expression levels of KLF4 transcriptional targets, including late differentiation markers, were reduced in HPV E6 and E7 rafts compared to their levels in parental rafts. However, the HPV E7-mediated block in EBV replication correlated with delayed expression of early differentiation markers. Overall, this study reveals an HPV16-mediated block in EBV replication, through E7, that may facilitate EBV latency and long-term persistence in the tumor context.IMPORTANCE Using a model examining the establishment of EBV infection in HPV-immortalized tissues, we showed an HPV-induced interruption of the normal EBV life cycle reminiscent of a latent EBV infection. Our data support the notion that a persistent EBV epithelial infection depends upon preexisting cellular alterations and suggest the ability of HPV to promote such changes. More importantly, these findings introduce a model for how EBV coinfection may influence HPV-positive (HPV-pos) OSCC pathogenesis. Latently EBV-infected epithelial cells, as well as other EBV-associated head-and-neck carcinomas, exhibit oncogenic phenotypes commonly seen in HPV-pos OSCC. Therefore, an HPV-induced shift in the EBV life cycle toward latency would not only facilitate EBV persistence but also provide additional viral oncogene expression, which can contribute to the rapid progression of HPV-pos OSCC. These findings provide a step toward defining a role for EBV as a cofactor in HPV-positive oropharyngeal tumors.
| S-EPMC6321917 | biostudies-literature
Project description:BackgroundThe etiopathogenesis of ocular surface squamous neoplasia (OSSN) is not fully understood. We assessed the frequency of oncogenic viruses in OSSN by immunohistochemistry (IHC) and polymerase chain reaction (PCR) for human papillomavirus (HPV), Epstein-Barr virus (EBV), Merkel cell polyomavirus (MCPyV), Kaposi sarcoma virus, and adenovirus. Cases from Zambia were prospectively enrolled using a cross-sectional study design between November 2017 and March 2020.MethodsDemographic and clinical data [age, sex, HIV status, antiretroviral therapy (ART) history, CD4 count, plasma viral load] and tumor biopsies were collected from 243 consenting patients. Tumor samples were bisected, and half was used for DNA isolation, while the other half was formalin fixed and paraffin embedded (FFPE) for histopathology analysis. The expressions of latent EBV nuclear antigen 1 (EBNA1), CDKN2A/p16INK4A (p16), and MCPyV large T-antigen (LT) were tested by IHC. Multiplex PCR was used to detect 16 HPV genotypes and four other DNA tumor viruses [Kaposi's sarcoma-associated herpesvirus (KSHV), EBV, MCPyV, and adenovirus]. Relationships between HIV status, viral DNA and protein expression, and tumor grades were determined by statistical analysis.ResultsOSSN tumors from patients were 29.6% preinvasive and 70.4% invasive. Patients presented with unilateral tumors that were 70.4% late stage (T3/T4). OSSN patients were HIV positive (72.8%). IHC on 243 FFPE biopsies resulted in the detection of EBNA1 (EBV), p16 high-risk HPV (HR-HPV), and MCPyV LT expression in 89.0%, 4.9%, and 0.0%, respectively. EBNA1 was expressed in all grades of preinvasive [cornea-conjunctiva intraepithelial neoplasia (CIN)1, 100%; CIN2, 85.7%; CIN3, 95.8%; and carcinoma in situ (CIS), 83.8%] and in invasive (89.2%) OSSN. PCR on 178 samples detected EBV, HR-HPV, and MCPyV in 80.3%, 9.0%, and 13.5% of tumors, respectively. EBV was detected in all grades of preinvasive and invasive OSSN. EBV detection was associated with high HIV viral loads (p = 0.022). HR-HPV was detected in 0.0% CIN1, 0.0% CIN2, 5.6% CIN3, 13.0% CIS, and 7.0% invasive OSSN.ConclusionsOur findings of EBV DNA and EBNA1 protein in all the grades of preinvasive and especially invasive OSSN are consistent with a potential causal role for EBV in OSSN. A role of HPV in OSSN was not clearly established in this study.
| S-EPMC9047892 | biostudies-literature
Project description:Epstein-Barr virus-positive ulcer (EBV + U) is a recently reported B cell lymphoproliferative disorder in the oral cavity, oropharynx, gastrointestinal tract and skin, principally in immunosuppressed patients. A 53-year-old female patient with rheumatoid arthritis treated with methotrexate, presenting ulcers of unknown duration on the dorsum and the lateral left border of the tongue. Excisional biopsy, histopathological analysis and histochemical stains for syphilis (Warthin-Starry), mycotic diseases (Grocott silver methenamine), tuberculosis (Ziehl-Neelsen), immunohistochemistry tests for herpesvirus type 8 (CMV), EBV (LMP-1) and DNA extraction for polymerase chain reaction (PCR) assay to CMV, EBV and herpes simplex virus-1 were performed. Posterior to PCR assay, the final diagnosis was EBV + U in the oral cavity. Acyclovir® was prescribed, showing clinical improvement. A case of EBV + U with clinical characteristics similar to other lesions or conditions has been reported. Special assays are necessary for an accurate diagnosis and treatment.
| S-EPMC8123244 | biostudies-literature
Project description:BACKGROUND: Multiple viruses, including human immunodeficiency virus, Epstein Barr virus (EBV) and mouse mammary tumour virus have been identified in human milk. High risk human papillomavirus (HPV) sequences have been identified in breast cancer. The aim of this study is to determine if viral sequences are present in human milk from normal lactating women. FINDINGS: Standard (liquid) and in situ polymerase chain reaction (PCR) techniques were used to identify HPV and EBV in human milk samples from normal lactating Australian women who had no history of breast cancer.High risk human papillomavirus was identified in milk samples of 6 of 40 (15%) from normal lactating women - sequencing on four samples showed three were HPV 16 and one was HPV 18. Epstein Barr virus was identified in fourteen samples (33%). CONCLUSION: The presence of high risk HPV and EBV in human milk suggests the possibility of milk transmission of these viruses. However, given the rarity of viral associated malignancies in young people, it is possible but unlikely, that such transmission is associated with breast or other cancers.
| S-EPMC3492016 | biostudies-literature
Project description:Background Epstein-Barr virus (EBV) glycoprotein 42 (gp42) enters B lymphocytes by binding to the human leukocyte antigen II (HLA-II) on their surface, in a process involving other EBV proteins (e.g., gH/gL and gp350). From a latent state of infection, the virus may reactivate and enter into a rapid proliferation phase, which enables the further entry of EBV into B lymphocytes and epithelial cells, leading to tumor development. EBV is an oncogenic virus associated with Hodgkin lymphoma (HL), and gp42 is a key protein in EBV infection of B lymphocytes. However, the exact binding pattern and capacity of gp42 are unclear. Methods The patterns and morphologies of gp42 binding to HLA-DPB1 were obtained through molecular dynamics simulation. The binding efficiency of gp42 and HLA-DPB1 was verified by plasmid construction and flow cytometry. Results The β-chain of HLA-DPB1 and the α-chain of gp42 formed a hydrogen-bonded complex, which was a hydrophilic protein with a resolution of 3.25. The binding efficiency between HLA-DPB1 and gp42 reached its peak (range, 26–31.3%) at a gp42 protein concentration of 80 µg. Conclusions We can inhibit the binding of gp42 to HLA-DPB1 by reducing the concentration of gp42. In the subsequent experiments, we will verify whether the binding of gp42 to HLA-DPB1 can be prevented by breaking hydrogen bonds and destroying hydrophilicity. These data may provide certain reference value for the development and treatment of Hodgkin’s lymphoma.
| S-EPMC8798132 | biostudies-literature
Project description:OBJECTIVE: To investigate Epstein-Barr virus (EBV) oral shedding frequency and EBV genetic diversity in pediatric patients with multiple sclerosis (MS). METHODS: This was a prospective case-control study. We used PCR-based assays to detect viral DNA in the monthly mouth swabs of 22 pediatric patients with MS and 77 age- and sex-matched healthy controls. EBV-positive samples were further analyzed for sequence variation in the EBV BCRF1 (ebvIL-10) gene using direct DNA sequencing methods, and in the EBV LMP1 gene by mass spectrometry. RESULTS: Nineteen of the 22 (86.4%) children with MS were seropositive for remote EBV infection compared to 35 out of 77 (45.5%) healthy controls (p = 0.008). Baseline analysis of mouth swabs revealed a higher proportion of EBV-positive samples from EBV-seropositive patients with MS compared to EBV-seropositive healthy controls (52.6% vs 20%, p = 0.007). Longitudinal analysis of monthly swabs revealed average EBV detection rates of 50.6% in patients with MS and 20.4% in controls (p = 0.01). The oral shedding frequencies of Herpesviruses herpes simplex virus-1, cytomegalovirus, human herpesvirus (HHV)-6, and HHV-7 did not differ between groups. Changes in the predominant EBV genetic variants were detected more frequently in patients with MS; however, no specific EBV genetic variant was preferentially associated with MS. CONCLUSION: Children with MS demonstrate abnormally increased rates of EBV viral reactivation and a broader range of genetic variants, suggesting a selective impairment in their immunologic control of EBV.
| S-EPMC3806908 | biostudies-literature