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Meta-analysis of nasopharyngeal carcinoma microarray data explores mechanism of EBV-regulated neoplastic transformation.

ABSTRACT: BACKGROUND: Epstein-Barr virus (EBV) presumably plays an important role in the pathogenesis of nasopharyngeal carcinoma (NPC), but the molecular mechanism of EBV-dependent neoplastic transformation is not well understood. The combination of bioinformatics with evidences from biological experiments paved a new way to gain more insights into the molecular mechanism of cancer. RESULTS: We profiled gene expression using a meta-analysis approach. Two sets of meta-genes were obtained. Meta-A genes were identified by finding those commonly activated/deactivated upon EBV infection/reactivation. These genes could be key players for pathways de-regulated by EBV during latent infection and lytic proliferation. Meta-B genes were obtained from differential genes commonly expressed in NPC and PEL (primary effusion lymphoma). We then integrated meta-A, meta-B and associated factors into an interaction network using acquired information. Our analysis suggests that NPC transformation depends on timely regulation of DEK, CDK inhibitor(s), p53, RB and several transcriptional cascades, interconnected by E2F, AP-1, NF-kappaB, STAT3 among others during latent and lytic cycles. CONCLUSION: In conclusion, our meta-analysis strategy re-analyzed EBV-related tumor data sets and identified sets of meta-genes possibly involved in maintaining latent or switching to lytic cycles of EBV in NPC. The results of this analysis may shed new lights to further our understanding of the EBV-led neoplastic transformation.

SUBMITTER: Chen X

PROVIDER: S-EPMC2491640 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Meta-analysis of nasopharyngeal carcinoma microarray data explores mechanism of EBV-regulated neoplastic transformation.

Chen Xia X Liang Shuang S Zheng WenLing W Liao ZhiJun Z Shang Tao T Ma WenLi W

BMC genomics 20080707

<h4>Background</h4>Epstein-Barr virus (EBV) presumably plays an important role in the pathogenesis of nasopharyngeal carcinoma (NPC), but the molecular mechanism of EBV-dependent neoplastic transformation is not well understood. The combination of bioinformatics with evidences from biological experiments paved a new way to gain more insights into the molecular mechanism of cancer.<h4>Results</h4>We profiled gene expression using a meta-analysis approach. Two sets of meta-genes were obtained. Met ...[more]

PMID: 18605998

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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.

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.

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Meta-analysis of nasopharyngeal carcinoma microarray data explores mechanism of EBV-regulated neoplastic transformation.

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Meta-analysis of nasopharyngeal carcinoma microarray data explores mechanism of EBV-regulated neoplastic transformation.

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