Differential regulation of miR-21 and miR-146a by Epstein–Barr virus-encoded EBNA2

Rosato, Paola; Anastasiadou, Eleni; Garg, Neha; Lenze, Dido; Boccellato, Francesco; Vincenti, Sara; Severa, Martina; Coccia, Eliana M.; Bigi, Rachele; Cirone, Mara; Ferretti, Elisabetta; Campese, Antonio Francesco; Hummel, Michael; Frati, Luigi; Presutti, Carlo; Faggioni, Alberto; Trivedi, Pankaj

doi:10.1038/leu.2012.108

Cited by 86 publications

(80 citation statements)

References 48 publications

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“…MiR-222, miR-223, the miR-17~92 cluster, and miR-155 are associated with the differentiation of T cells (Riley et al, 2012;Poole and Sinclair, 2015;Saki et al, 2015). EBV-encoded EBNA2 induces the expression of miR-21, consequently promoting B cell transformation and driving the antiviral immune response (Rosato et al, 2012;Zhu et al, 2013). The upregulation of miR-127 in EBV-positive Burkitt's lymphoma may cause the downregulation of the B cell markers, B lymphocyte-induced maturation protein 1 (BLIMP-1) and X-box binding protein 1 (XBP-1) (Onnis et al, 2012).…”

Section: Ebv Latent Proteins Dysregulate Host Mirnas To Regulate the mentioning

confidence: 99%

An update: Epstein-Barr virus and immune evasion via microRNA regulation

Zuo

Yue

et al. 2017

Virol. Sin.

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Epstein-Barr virus (EBV) is an oncogenic virus that ubiquitously establishes life-long persistence in humans.To ensure its survival and maintain its B cell transformation function, EBV has developed powerful strategies to evade host immune responses. Emerging evidence has shown that microRNAs (miRNAs) are powerful regulators of the maintenance of cellular homeostasis. In this review, we summarize current progress on how EBV utilizes miRNAs for immune evasion. EBV encodes miRNAs targeting both viral and host genes involved in the immune response. The miRNAs are found in two gene clusters, and recent studies have demonstrated that lack of these clusters increases the CD4 + and CD8 + T cell response of infected cells. These reports strongly indicate that EBV miRNAs are critical for immune evasion. In addition, EBV is able to dysregulate the expression of a variety of host miRNAs, which influence multiple immune-related molecules and signaling pathways. The transport via exosomes of EBV-regulated miRNAs and viral proteins contributes to the construction and modification of the inflammatory tumor microenvironment. During EBV immune evasion, viral proteins, immune cells, chemokines, pro-inflammatory cytokines, and pro-apoptosis molecules are involved. Our increasing knowledge of the role of miRNAs in immune evasion will improve the understanding of EBV persistence and help to develop new treatments for EBV-associated cancers and other diseases.

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Section: Ebv Latent Proteins Dysregulate Host Mirnas To Regulate the mentioning

confidence: 99%

An update: Epstein-Barr virus and immune evasion via microRNA regulation

Zuo

Yue

et al. 2017

Virol. Sin.

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“…63 Overexpression of miR-21 has been found to promote tumor progression and invasion in solid tumors via targeting PTEN. 64,65 Mir-146a has ben shown to inhibit the NF-kB pathway in the NK/T-cell lymphoma cell lines.…”

Section: Genetic and Mirna Profilementioning

confidence: 99%

EBV-positive diffuse large B-cell lymphoma of the elderly

Papathomas

Medeiros

et al. 2013

Blood

199

179

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Epstein-Barr virus (EBV) positive diffuse large B-cell lymphoma (DLBCL) of the elderly, initially described in 2003, is a provisional entity in the 2008 World Health Organization classification system and is defined as an EBV-positive monoclonal large B-cell proliferation that occurs in patients >50 years of age and in whom there is no known immunodeficiency or history of lymphoma. These tumors are more common in Asia but also occur in North America and Europe at a low frequency. These neoplasms exhibit a morphologic continuum, from polymorphous to monomorphous, but morphologic features do not correlate with prognosis as all patients have a clinically aggressive course. Most EBV-positive DLBCL of the elderly patients have an activated B-cell immunophenotype and are characterized by prominent nuclear factor-κB activation. Cytogenetic complexity is usually low. In this review, we comprehensively delineate the data emerging from analyses of EBV latency program, microRNA-mediated EBV viral oncogenesis, functional genomics of EBV and its biology, and differential diagnosis challenge for EBV-positive DLBCL of the elderly. It is hoped that the improved understanding of these tumors will lead to the development of novel therapeutic approaches, enhance the effectiveness of clinical trials, and improve prognosis.

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“…EBV LMP1, which contributes to cell transformation, has been shown to affect the levels of induction of several miRNAs, including miR-146a (37). Similarly, the EBV latency protein EBNA2 alters the levels of some cellular miRNAs, in particular, upregulating miR-21 and downregulating miR-146a (38). Cellular miRNAs can also affect the balance between EBV latent and lytic infection.…”

mentioning

confidence: 99%

Epstein-Barr Virus EBNA1 Protein Regulates Viral Latency through Effects on let-7 MicroRNA and Dicer

Mansouri

Pan

Blencowe

et al. 2014

J Virol

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The EBNA1 protein of Epstein-Barr virus (EBV) plays multiple roles in EBV latent infection, including altering cellular pathways relevant for cancer. Here we used microRNA (miRNA) cloning coupled with high-throughput sequencing to identify the effects of EBNA1 on cellular miRNAs in two nasopharyngeal carcinoma cell lines. EBNA1 affected a small percentage of cellular miRNAs in both cell lines, in particular, upregulating multiple let-7 family miRNAs, including let-7a. The effects of EBNA1 on let-7a were verified by demonstrating that EBNA1 silencing in multiple EBV-positive carcinomas downregulated let-7a. Accordingly, the let-7a target, Dicer, was found to be partially downregulated by EBNA1 expression (at the mRNA and protein levels) and upregulated by EBNA1 silencing in EBV-positive cells. Reporter assays based on the Dicer 3= untranslated region with and without let-7a target sites indicated that the effects of EBNA1 on Dicer were mediated by let-7a. EBNA1 was also found to induce the expression of let-7a primary RNAs in a manner dependent on the EBNA1 transcriptional activation region, suggesting that EBNA1 induces let-7a by transactivating the expression of its primary transcripts. Consistent with previous reports that Dicer promotes EBV reactivation, we found that a let-7a mimic inhibited EBV reactivation to the lytic cycle, while a let-7 sponge increased reactivation. The results provide a mechanism by which EBNA1 could promote EBV latency by inducing let-7 miRNAs. IMPORTANCE The EBNA1 protein of Epstein-Barr virus (EBV) contributes in multiple ways to the latent mode of EBV infection that leads to lifelong infection.In this study, we identify a mechanism by which EBNA1 helps to maintain EBV infection in a latent state. This involves induction of a family of microRNAs (let-7 miRNAs) that in turn decreases the level of the cellular protein Dicer. We demonstrate that let-7 miRNAs inhibit the reactivation of latent EBV, providing an explanation for our previous observation that EBNA1 promotes latency. In addition, since decreased levels of Dicer have been associated with metastatic potential, EBNA1 may increase metastases by downregulating Dicer. E pstein-Barr virus (EBV) is a gammaherpesvirus that infects most people worldwide and is associated with several types of B-cell lymphomas, as well as nasopharyngeal carcinoma (NPC) and gastric carcinoma (1, 2). The EBV life cycle consists of both latent and lytic modes of infection in B lymphocytes and epithelial cells. Although EBV mainly exists in a latent mode of infection in B cells, it occasionally reactivates to the lytic state for cell-to-cell spread. In addition, lytic reactivation of EBV in epithelial cells of the orthopharynx is necessary for the production of viral particles required for host-to-host transmission of the virus. Lytic infection begins with the expression of BZLF1 (or Zta), followed by the expression of BRLF1 (or Rta). Together these proteins activate the cascade of subsequent lytic gene expression and enable the generation of lin...

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Differential regulation of miR-21 and miR-146a by Epstein–Barr virus-encoded EBNA2

Cited by 86 publications

References 48 publications

An update: Epstein-Barr virus and immune evasion via microRNA regulation

An update: Epstein-Barr virus and immune evasion via microRNA regulation

EBV-positive diffuse large B-cell lymphoma of the elderly

Epstein-Barr Virus EBNA1 Protein Regulates Viral Latency through Effects on let-7 MicroRNA and Dicer

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