Epstein–Barr virus maintains lymphomas via its miRNAs

Vereide, David T.; Seto, Eri; Chiu, Ya-Fang; Hayes, Mitchell; Tagawa, Takanobu; Grundhoff, Adam; Hammerschmidt, Wolfgang; Sugden, Bill

doi:10.1038/onc.2013.71

Cited by 142 publications

(160 citation statements)

References 30 publications

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“…T cell-derived CD40 signaling may also help to induce IRF4 expression in LMP1-KO EBVinduced lymphomas (35). Finally, the viral encoded microRNAs (a portion of which are expressed by the B95.8 strain of EBV) were recently shown to promote the survival of BLs by inhibiting apoptosis (11), and likely contribute to the survival of LMP1-KO EBV-induced lymphomas.…”

Section: Methodsmentioning

confidence: 99%

“…Although LMP1 is essential for the long-term outgrowth of EBV-transformed LCLs in vitro in the absence of a feeder layer (9), EBV-positive lymphomas in vivo often have more restricted forms of viral latency. For example, EBV-positive BLs, which are largely driven by MYC translocations, usually express only the EBNA1 protein (required for latent EBV genome maintenance), in addition to the virally encoded microRNAs and EBV-encoded small nuclear RNAs (EBER) (1,2,10,11). Furthermore, the majority of EBV-positive AIDS-related DLBCLs do not express detectable LMP1 protein (12).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

LMP1-deficient Epstein-Barr virus mutant requires T cells for lymphomagenesis

Dong¹,

Xu²,

Plowshay³

et al. 2014

J. Clin. Invest.

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formation comparison, the P value was calculated using a 2-tailed Fisher exact test. For viral load comparison, the P value was calculated using the Wilcoxon rank-sum test. A P value less than 0.05 was considered significant.Study approval. All animal experiments were approved by the University of Wisconsin-Madison IACUC and conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals. For human AIDS-related lymphomas, cases were collected from the Department of Pathology and Laboratory Medicine of Weill Cornell Medical College. All human samples, obtained with IRB and biospecimen use approval, were residual cases after diagnosis.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

LMP1-deficient Epstein-Barr virus mutant requires T cells for lymphomagenesis

Dong¹,

Xu²,

Plowshay³

et al. 2014

J. Clin. Invest.

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“…Those that are encoded by EBV itself include BALF5 (21), LMP1 (22), LMP2A (23), and BHRF1 (23,24). Previously identified cellular targets include Bim (25), CAPRIN2 (24), CASP3 (26), DAZAP2 (27), DICER1 (28), E-cadherin (29), IPO7 (26,30), and PUMA (31). Many other candidate target genes have been identified by miRNA targetome studies (24,27,30,32); the biological significances of these miRNA-target interactions have yet to be clarified.…”

mentioning

confidence: 99%

Clustered MicroRNAs of the Epstein-Barr Virus Cooperatively Downregulate an Epithelial Cell-Specific Metastasis Suppressor

Kanda

Miyata

Kano

et al. 2015

J Virol

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The Epstein-Barr virus (EBV) encodes its own microRNAs (miRNAs);Although in vitro reporter assays identified BART22 as being responsible for the NDRG1 downregulation, EBV genetic analyses revealed that BART22 was not solely responsible; rather, the entire BART miRNA cluster 2 was responsible for the downregulation. Immunohistochemical analyses revealed that the expression level of the NDRG1 protein was downregulated significantly in EBV-positive nasopharyngeal carcinoma specimens. Considering that NDRG1 encodes an epithelial differentiation marker and a suppressor of metastasis, these data implicate a causative relationship between BART miRNA expression and epithelial carcinogenesis in vivo. IMPORTANCEEBV-related epithelial cancers, such as nasopharyngeal carcinomas and EBV-positive gastric cancers, encompass more than 80% of EBV-related malignancies. Although it is known that they express high levels of virally encoded BART miRNAs, how these miRNAs contribute to EBV-mediated epithelial carcinogenesis remains unknown. Although a number of screenings have been performed to identify targets of viral miRNAs, many targets likely have not been identified, especially in case of epithelial cell infection. This is the first study to use EBV genetics to perform unbiased screens of cellular genes that are differentially expressed in viral miRNA-positive and -negative epithelial cells. The result indicates that multiple EBV-encoded miRNAs cooperatively downregulate NDRG1, an epithelial differentiation marker and suppressor of metastasis. The experimental system described in this study should be useful for further clarifying the mechanism of EBV-mediated epithelial carcinogenesis. T he Epstein-Barr virus (EBV) is a common herpesvirus that is widespread in all human populations. Primary EBV infections in adolescence often manifest as infectious mononucleosis (1).EBV infection is also associated with several types of lymphomas and epithelial malignancies. The B95-8 strain of EBV, an infectious mononucleosis-derived isolate, is biologically indistinguishable from other isolates of EBV in that it efficiently produces progeny virus and transforms peripheral B-lymphocytes in vitro (2). The marmoset lymphoblastoid B95-8 cell line is one of the most widely used EBV-producing cell lines. Although the B95-8 strain was assumed to be a prototype EBV, restriction mapping and DNA sequencing analyses revealed that its genome contains a deletion of approximately 12 kb (3-5). This deleted region is apparently dispensable for progeny virus production and B-cell transformation; hence, its importance has been underestimated.The recent discovery of EBV-encoded microRNA (miRNA) genes within the 12-kb region has dramatically changed the situation. The initial discovery of five EBV miRNAs was followed by the subsequent identification of a number of additional miRNAs (6-9); to date, 44 mature miRNAs have been identified, of which 4 are encoded at the BHRF1 locus, and 40 are encoded at the BART locus. A complete list of EBV miRNAs, includin...

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“…Studies of EBV genomic deletions revealed that several miRNAs expressed from the BHRF1 locus (miRBHRF1s) play critical roles in B-cell transformation by inhibiting apoptosis and promoting cell cycle progression (Seto et al 2010;Feederle et al 2011). Consistently, expression of EBV miRNAs from the BamHI A rightward transcript (BART) locus is sufficient to prevent apoptosis in Burkitt's lymphoma (BL) cells or transformed primary B lymphocytes that have lost the EBV genome (Vereide et al 2014). Similarly, genetic deletion and complementation studies of KSHV miRNAs have shown that they promote cell cycle progression and inhibit apoptosis, necessary for cellular transformation (Moody et al 2013).…”

Section: Viral Mirnas: Small Rnas Big Rolesmentioning

confidence: 85%

Viral noncoding RNAs: more surprises

et al. 2015

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Eukaryotic cells produce several classes of long and small noncoding RNA (ncRNA). Many DNA and RNA viruses synthesize their own ncRNAs. Like their host counterparts, viral ncRNAs associate with proteins that are essential for their stability, function, or both. Diverse biological roles—including the regulation of viral replication, viral persistence, host immune evasion, and cellular transformation—have been ascribed to viral ncRNAs. In this review, we focus on the multitude of functions played by ncRNAs produced by animal viruses. We also discuss their biogenesis and mechanisms of action.

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Epstein–Barr virus maintains lymphomas via its miRNAs

Cited by 142 publications

References 30 publications

LMP1-deficient Epstein-Barr virus mutant requires T cells for lymphomagenesis

LMP1-deficient Epstein-Barr virus mutant requires T cells for lymphomagenesis

Clustered MicroRNAs of the Epstein-Barr Virus Cooperatively Downregulate an Epithelial Cell-Specific Metastasis Suppressor

Viral noncoding RNAs: more surprises

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