The Epstein-Barr virus miR-BHRF1 microRNAs regulate viral gene expression in cis

Poling, Brigid Chiyoko; Price, Alexander M.; Luftig, Micah A.; Cullen, Bryan R.

doi:10.1016/j.virol.2017.09.015

Cited by 23 publications

(23 citation statements)

References 64 publications

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“…In different host cells, the expression profile of these viral miRNAs could be different and may serve as biomarkers for EBV-associated diseases (34)(35)(36)(37). Consistent with previous studies, which showed that the expression of miRNA from the miR-BHRF1 cluster was relatively restricted to lytic and latency III phases of EBV-infected B lymphoma cells (36,(38)(39)(40)(41)(42), we also observed that the miR-BHRF1 cluster is highly expressed in EBV-immortalized LCL cells and responds to LA treatment. In contrast, miR-BART induces tumor metastasis by regulating PTEN-dependent pathways and acts as a biomarker in nasopharyngeal carcinoma (33,43), suggesting a tissue-specific pathogenic role of the miR-BHRF1 cluster that regulates the development of EBV-associated B lymphoma malignancies in response to LA.…”

supporting

confidence: 88%

Lactic Acid Downregulates Viral MicroRNA To Promote Epstein-Barr Virus-Immortalized B Lymphoblastic Cell Adhesion and Growth

Wei

Yin

et al. 2018

J Virol

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High plasma lactate is associated with poor prognosis of many malignancies, but its role in virally mediated cancer progression and underlying molecular mechanisms are unclear. Epstein-Barr virus (EBV), the first human oncogenic virus, causes several cancers, including B-cell lymphoma. Here, we report that lactate dehydrogenase A (LDH-A) expression and lactate production are elevated in EBV-immortalized B lymphoblastic cells, and lactic acid (LA; acidic lactate) at low concentration triggers EBV-infected B-cell adhesion, morphological changes, and proliferation and Moreover, LA-induced responses of EBV-infected B cells uniquely occurs in viral latency type III, and it is dramatically associated with the inhibition of global viral microRNAs, particularly the miR-BHRF1 cluster, and the high expression of ,, and genes. The introduction of miR-BHRF1-1 blocks the LA-induced effects of EBV-infected B cells. Thus, this may be a novel mechanism to explain EBV-immortalized B lymphoblastic cell malignancy in an LA microenvironment. The tumor microenvironment is complicated, and lactate, which is created by cell metabolism, contributes to an acidic microenvironment that facilitates cancer progression. However, how LA operates in virus-associated cancers is unclear. Thus, we studied how EBV (the first tumor virus identified in humans; it is associated with many cancers) upregulates the expression of LDH-A and lactate production in B lymphoma cells. Elevated LA induces adhesion and the growth of EBV-infected B cells by inhibiting viral microRNA transcription. Thus, we offer a novel understanding of how EBV utilizes an acidic microenvironment to promote cancer development.

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supporting

confidence: 88%

Lactic Acid Downregulates Viral MicroRNA To Promote Epstein-Barr Virus-Immortalized B Lymphoblastic Cell Adhesion and Growth

Wei

Yin

et al. 2018

J Virol

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“…Studies also found that EBV miRNAs can inhibit EBNA1 expression, which may be EBV miRNAs a means to assist the host to escape immune surveillance [47]. In addition, EBV miR-BART6-5p was found to inhibit EBNA2 expression [48], and EBV-miR-BHRF1s could inhibit EBNA2 co-activated antigen EBNA-LP expression [49], suggesting that EBNAs and EBNA-LP could be regulated by EBV miRNAs to avoid immune surveillance and maintain EBV latency.…”

Section: Antigen Expressionmentioning

confidence: 97%

Epstein barr virus encodes miRNAs to assist host immune escape

Yang

et al. 2020

J. Cancer

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Epstein-barr virus (EBV) is a definite tumorigenic virus, which can form lifelong latency in the host, which is difficult to be recognized and completely eliminated by the immune system. It is closely related to the occurrence and development of nasopharyngeal cancer, gastric cancer and various types of lymphoma. At present, a total of 44 Epstein-barr virus-encoded microRNAs (EBV miRNAs) have been found. In response to the immune system of the body, EBV miRNAs can inhibit the expression and presentation of viral antigens, inhibit immune activation and immunotoxicity, assisting host cells to escape from immunity, and providing conditions for further immortalized tumorigenesis of the host cells.

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“…In addition to the regulation of lytic replication via down-regulation of BZLF1 and BRLF1 by BART miRNAs 82 , they have also been described to limit EBNA2, LMP1 and LMP2 expression [103][104][105][106] . In addition, BHRF1 miRNAs optimize the timing of EBNA-LP and BHRF1 expression for optimal B cell transformation 107,108 and suppress sumoylation that is required for efficient lytic replication induction 109 . Finally, both BART and BHRF1 miRNAs attenuate B cell receptor signaling and thereby desensitize infected B cells to lytic EBV replication induction 110 .…”

Section: Non-translated Rnas and Tumorigenesismentioning

confidence: 99%

Latency and lytic replication in Epstein–Barr virus-associated oncogenesis

2019

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Epstein-Barr virus (EBV) was the first tumour virus identified in humans. The virus is primarily associated with lymphomas and epithelial cell cancers. These tumours express latent EBV antigens and the oncogenic potential of individual latent EBV proteins has been extensively explored. Nevertheless, it was presumed that the pro-proliferative and anti-apoptotic functions of these oncogenes allow the virus to persist in humans; however, recent evidence suggests that cellular transformation is not required for virus maintenance. Vice versa, lytic EBV replication was assumed to destroy latently infected cells and thereby inhibit tumorigenesis, but at least the initiation of the lytic cycle has now been shown to support EBV-driven malignancies. In addition to these changes in the roles of latent and lytic EBV proteins during tumorigenesis, the function of non-coding RNAs has become clearer, suggesting that they might mainly mediate immune escape rather than cellular transformation. In this Review, these recent findings will be discussed with respect to the role of EBV-encoded oncogenes in viral persistence and the contributions of lytic replication as well as non-coding RNAs in virus-driven tumour formation. Accordingly, early lytic EBV antigens and attenuated viruses without oncogenes and microRNAs could be harnessed for immunotherapies and vaccination. AbstractEpstein-Barr virus (EBV) was the first tumor virus identified in humans. It is primarily associated with lymphomas and epithelial cell cancers. These tumors express latent EBV antigens and the oncogenic potential of individual latent EBV proteins has been extensively explored.Nevertheless, it was presumed that the pro-proliferative and anti-apoptotic functions of these oncogenes allow the virus to persist in humans; however, recent evidence suggests that cellular transformation is not required for virus maintenance. Vice versa, lytic EBV replication was assumed to destroy latently infected cells and thereby inhibit tumorigenesis, but at least the initiation of the lytic cycle has now been shown to support EBV-driven malignancies. In addition to these changes in the roles of latent and lytic EBV proteins during tumourigenesis, the function of non-translated RNAs has become clearer, suggesting that they might mainly mediate immune escape rather than cellular transformation. In this Review, these recent findings will be discussed with respect to the role of EBV-encoded oncogenes in viral persistence and the contributions of lytic replication as well as non-translated RNAs in virus-driven tumor formation. Accordingly, early lytic EBV antigens and attenuated viruses without oncogenes and miRNAs could be harnessed for immunotherapies and vaccination. Table of contents blurb (40-50 words max.)Epstein-Barr virus (EBV) establishes latent and persistent infections in humans, and is associated with several cancers. In this Review, Münz discusses the evidence for EBV persistence without B cell transformation and the role of early abortive lytic replication, as well as non...

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The Epstein-Barr virus miR-BHRF1 microRNAs regulate viral gene expression in cis

Cited by 23 publications

References 64 publications

Lactic Acid Downregulates Viral MicroRNA To Promote Epstein-Barr Virus-Immortalized B Lymphoblastic Cell Adhesion and Growth

Lactic Acid Downregulates Viral MicroRNA To Promote Epstein-Barr Virus-Immortalized B Lymphoblastic Cell Adhesion and Growth

Epstein barr virus encodes miRNAs to assist host immune escape

Latency and lytic replication in Epstein–Barr virus-associated oncogenesis

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