The Epstein Barr-encoded BART-6-3p microRNA affects regulation of cell growth and immuno response in Burkitt lymphoma

Ambrosio, Maria Raffaella; Navari, Mohsen; Lisio, Lorena Di; Andrés-León, Eduardo; Onnis, Anna; Gazaneo, Sara; Mundo, Lucia; Ulivieri, Cristina; Gómez, Gonzalo Vázquez; Lazzi, Stefano; Piris, Miguel Á.; Leoncini, Lorenzo; Falco, Giulia De

doi:10.1186/1750-9378-9-12

Cited by 65 publications

(64 citation statements)

References 45 publications

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“…Our data shows that the mRNA transcription of PTEN itself is not significantly differentially expressed between EBV positive and negative BLs. However, Ambrosio et al found that protein levels of PTEN are significantly lower in EBV positive BLs compared to negatives (53). This suggests a mechanism in which viral miRNAs interact with PTEN causing a translational inhibition.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Transcriptome and Mutational Profiling of Endemic Burkitt Lymphoma Reveals EBV Type–Specific Differences

Kaymaz

Oduor

et al. 2017

Molecular Cancer Research

100

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Endemic Burkitt lymphoma (eBL) is the most common pediatric cancer in malaria-endemic equatorial Africa and nearly always contains Epstein-Barr virus (EBV), unlike sporadic Burkitt Lymphoma (sBL) that occurs with a lower incidence in developed countries. Given these differences and the variable clinical presentation and outcomes, we sought to further understand pathogenesis by investigating transcriptomes using RNA sequencing (RNAseq) from multiple primary eBL tumors compared to sBL tumors. Within eBL tumors, minimal expression differences were found based on: anatomical presentation site, in-hospital survival rates, and EBV genome type; suggesting that eBL tumors are homogeneous without marked subtypes. The outstanding difference detected using surrogate variable analysis was the significantly decreased expression of key genes in the immunoproteasome complex (PSMB9/β1i, PSMB10/β2i, PSMB8/β5i, and PSME2/PA28β) in eBL tumors carrying type 2 EBV compared to type 1 EBV. Secondly, in comparison to previously published pediatric sBL specimens, the majority of the expression and pathway differences was related to the PTEN/PI3K/mTOR signaling pathway and was correlated most strongly with EBV status rather than geographic designation. Third, common mutations were observed significantly less frequently in eBL tumors harboring EBV type 1, with mutation frequencies similar between tumors with EBV type 2 and without EBV. In addition to the previously reported genes, a set of new genes mutated in BL including TFAP4, MSH6, PRRC2C, BCL7A, FOXO1, PLCG2, PRKDC, RAD50, and RPRD2 were identified. Overall, these data establish that EBV, particularly EBV type 1, supports BL oncogenesis alleviating the need for certain driver mutations in the human genome.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Transcriptome and Mutational Profiling of Endemic Burkitt Lymphoma Reveals EBV Type–Specific Differences

Kaymaz

Oduor

et al. 2017

Molecular Cancer Research

100

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“…In this study, we chose BART6-3p as our study object, which is highly expressed in latency II malignancy and plays a role in tumorigenesis [43][44][45][46] , but has no clear functions related to immune regulation. By using a cDNA microarray technique, we found that 49 genes were downregulated upon BART6-3p mimic transfection in PBMCs, which are natural host cells of EBV infection, and most of them participated in the type I IFN virus response, as well as the RIG-I-like receptor signaling.…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr Virus miR-BART6-3p Inhibits the RIG-I Pathway

Lu¹,

Qin²,

Jia³

et al. 2017

J Innate Immun

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Recognition of viral pathogen-associated molecular patterns by pattern recognition receptors (PRRs) is the first step in the initiation of a host innate immune response. As a PRR, RIG-I detects either viral RNA or replication transcripts. Avoiding RIG-I recognition is a strategy employed by viruses for immune evasion. Epstein-Barr virus (EBV) infects the majority of the human population worldwide. During the latent infection period there are only a few EBV proteins expressed, whereas EBV-encoded microRNAs, such as BART microRNAs, are highly expressed. BART microRNAs regulate both EBV and the host's gene expression, modulating virus proliferation and the immune response. Here, through gene expression profiling, we found that EBV miR-BART6-3ps inhibited genes of RIG-I-like receptor signaling and the type I interferon (IFN) response. We demonstrated that miR-BART6-3p rather than other BARTs specifically suppressed RIG-I-like receptor signaling-mediated IFN-β production. RNA-seq was used to analyze the global transcriptome change upon EBV infection and miR-BART6-3p mimics transfection, which revealed that EBV infection-triggered immune response signaling can be repressed by miR-BART6-3p overexpression. Furthermore, miR-BART6-3p inhibited the EBV-triggered IFN-β response and facilitated EBV infection through targeting the 3′UTR of RIG-I mRNA. These findings provide new insights into the mechanism underlying the strategies employed by EBV to evade immune surveillance.

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“…Additionally, EBV miRNAs regulate the IFNγ-STAT1 pathway in EBV + NK cells by downregulating IFNγ transcriptional regulator T-bet (BART20-5p), IFNγ (BART20-5p), and STAT1 (BART8) (Huang and Lin 2014;Lin et al 2013). Inhibition of BART6-3p in a BL cell line caused upregulation of the IL-6 receptor chains (p80 and gp130) at the mRNA and protein level, indicating that BART6-3p may affect IL-6 signaling (Ambrosio et al 2014).…”

Section: Ebv Mirnasmentioning

confidence: 99%

“…These miRNAs are organized in Lerner et al (1981), Clarke et al (1991), Komano et al (1999), Nanbo et al (2002Nanbo et al ( , 2005, Ruf et al (2005) miR-BHRF1-3 Downregulates T cell attracting chemokine CXCL-11 Xia et al (2008) miR-BART2-5p Inhibition of this miRNA results in increased NK-cell killing in vitro Nachmani et al (2009) miR-BART15 Downregulates NLRP3 Haneklaus et al (2012) miR-BART20-5p Downregulates IFNγ transcriptional regulator T-bet and IFNγ Huang and Lin (2014), Lin et al (2013) miR-BART8 Inhibits STAT1 expression Huang and Lin (2014) miR-BART6-3p Downregulation of IL-6 receptor chains Ambrosio et al (2014) clusters and are expressed during all latency stages (and thus in EBV-associated tumors), although their expression levels differ between these stages (Amoroso et al 2011;Motsch et al 2012;Qiu et al 2011). miRNAs have been detected in EBV virions, allowing their release in newly infected cells (Jochum et al 2012a).…”

Section: Ebv Mirnasmentioning

confidence: 99%

Immune Evasion by Epstein-Barr Virus

Ressing

Gent

Gram

et al. 2015

Current Topics in Microbiology and Immunology

108

106

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Epstein-Bar virus (EBV) is widespread within the human population with over 90% of adults being infected. In response to primary EBV infection, the host mounts an antiviral immune response comprising both innate and adaptive effector functions. Although the immune system can control EBV infection to a large extent, the virus is not cleared. Instead, EBV establishes a latent infection in B lymphocytes characterized by limited viral gene expression. For the production of new viral progeny, EBV reactivates from these latently infected cells. During the productive phase of infection, a repertoire of over 80 EBV gene products is expressed, presenting a vast number of viral antigens to the primed immune system. In particular the EBV-specific CD4+ and CD8+ memory T lymphocytes can respond within hours, potentially destroying the virus-producing cells before viral replication is completed and viral particles have been released. Preceding the adaptive immune response, potent innate immune mechanisms provide a first line of defense during primary and recurrent infections. In spite of this broad range of antiviral immune effector mechanisms, EBV persists for life and continues to replicate. Studies performed over the past decades have revealed a wide array of viral gene products interfering with both innate and adaptive immunity. These include EBV-encoded proteins as well as small noncoding RNAs with immune-evasive properties. The current review presents an overview of the evasion strategies that are employed by EBV to facilitate immune escape during latency and productive infection. These evasion mechanisms may also compromise the elimination of EBV-transformed cells, and thus contribute to malignancies associated with EBV infection.

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The Epstein Barr-encoded BART-6-3p microRNA affects regulation of cell growth and immuno response in Burkitt lymphoma

Cited by 65 publications

References 45 publications

Comprehensive Transcriptome and Mutational Profiling of Endemic Burkitt Lymphoma Reveals EBV Type–Specific Differences

Comprehensive Transcriptome and Mutational Profiling of Endemic Burkitt Lymphoma Reveals EBV Type–Specific Differences

Epstein-Barr Virus miR-BART6-3p Inhibits the RIG-I Pathway

Immune Evasion by Epstein-Barr Virus

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