Expression of Viral MicroRNAs in Epstein-Barr Virus-Associated Gastric Carcinoma

Kim, Do Nyun; Chae, Hiun-Suk; Oh, Sang Taek; Kang, Jin‐Hyoung; Park, Cho Hyun; Park, Won Sang; Takada, Kenzo; Lee, Jae Myun; Lee, Won-Keun; Lee, Suk Kyeong

doi:10.1128/jvi.02271-06

Cited by 147 publications

(97 citation statements)

References 22 publications

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“…As large subsets of viral miRNAs are expressed in all phases of EBV's life cycle (48), it appears plausible that viral miRNAs inhibit these target molecules globally. For example, miRNAs miR-BART1, miR-BART2, and miR-BART22, which target IL-12 (35), are all highly expressed not only in latency III but also in EBV-infected germinal center B cells (latency II) and memory B cells (latency 0/I) from healthy donors as well as different types of EBV-associated cancer cells (34,48,49). Therefore, miRNA-mediated reduction of IL-12 could lead to decreased T-cell activation and recognition at different stages of infection and malignant disease.…”

Section: Discussionmentioning

confidence: 99%

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells

Albanese

Tagawa

Bouvet

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

127

133

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Infection with Epstein-Barr virus (EBV) affects most humans worldwide and persists life-long in the presence of robust virus-specific T-cell responses. In both immunocompromised and some immunocompetent people, EBV causes several cancers and lymphoproliferative diseases. EBV transforms B cells in vitro and encodes at least 44 microRNAs (miRNAs), most of which are expressed in EBV-transformed B cells, but their functions are largely unknown. Recently, we showed that EBV miRNAs inhibit CD4 + T-cell responses to infected B cells by targeting IL-12, MHC class II, and lysosomal proteases. Here we investigated whether EBV miRNAs also counteract surveillance by CD8 + T cells. We have found that EBV miRNAs strongly inhibit recognition and killing of infected B cells by EBV-specific CD8 + T cells through multiple mechanisms. EBV miRNAs directly target the peptide transporter subunit TAP2 and reduce levels of the TAP1 subunit, MHC class I molecules, and EBNA1, a protein expressed in most forms of EBV latency and a target of EBV-specific CD8 + T cells. Moreover, miRNAmediated down-regulation of the cytokine IL-12 decreases the recognition of infected cells by EBV-specific CD8 + T cells. Thus, EBV miRNAs use multiple, distinct pathways, allowing the virus to evade surveillance not only by CD4 + but also by antiviral CD8 + T cells.adaptive immunity | immune evasion | herpesvirus | CD8 T cells | microRNA E pstein-Barr virus (EBV) is a ubiquitous herpesvirus that infects the majority of the human population worldwide. Although EBV infection persists for life, most carriers remain asymptomatic due to a stringent control by virus-specific immunity. An important component of this immunity is EBV-specific CD8 + T cells, which often expand to high numbers in healthy carriers or after primary infection. Conversely, the absence of EBV-specific CD8 + T cells predicts the emergence of EBVassociated disease in patients after stem cell transplantation or when afflicted with AIDS (1-3). Dangerous EBV-mediated complications can be reversed or prevented by transfer of EBVspecific T cells (4, 5), which further confirms the important role of continuous T-cell control of EBV infection. Among EBVspecific T cells, CD8 + T cells predominate; about 0.05-1% of all CD8 + T cells in healthy donors are typically specific for EBV latent antigens and about twice as many for lytic antigens (6, 7).EBV predominantly infects B cells and establishes a latent infection before production of progeny virus becomes possible (8). Four distinct programs of EBV latent infection have been defined according to their expression profiles of latent viral genes (9-11). One of these programs, known as latency III or the "growth program," is characterized by the expression of a restricted set of approximately eight viral proteins, which activate B cells and drive their proliferation, thus increasing the viral reservoir. Latency III is found in EBV-associated malignancies in immunosuppressed patients (9) and likely reemerges continuously in healthy carriers (9, 12), indicati...

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Section: Discussionmentioning

confidence: 99%

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells

Albanese

Tagawa

Bouvet

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

127

133

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“…EBV is also associated with z6%-16% of gastric carcinoma cases. It was demonstrated that BART but not BHRF1 miRNAs are expressed in EBV-infected gastric carcinoma cell lines, in animal models, and in tumor samples from patients (Kim et al 2007). Viral miRNAs were found that recognize and target viral transcripts, as demonstrated for EBV-encoded miR-BART2 that down-regulates the viral DNA polymerase BALF5, which represent a mechanism of virus self-regulation (Barth et al 2008).…”

Section: Micrornas Encoded By Oncogenic Viruses: External Switches Tomentioning

confidence: 99%

Emerging roles of microRNAs as molecular switches in the integrated circuit of the cancer cell

Sotiropoulou¹,

Pampalakis²,

Lianidou³

et al. 2009

RNA

154

123

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Transformation of normal cells into malignant tumors requires the acquisition of six hallmark traits, e.g., self-sufficiency in growth signals, insensitivity to antigrowth signals and self-renewal, evasion of apoptosis, limitless replication potential, angiogenesis, invasion, and metastasis, which are common to all cancers (Hanahan and Weinberg 2000). These new cellular traits evolve from defects in major regulatory microcircuits that are fundamental for normal homeostasis. The discovery of microRNAs (miRNAs) as a new class of small non-protein-coding RNAs that control gene expression post-transcriptionally by binding to various mRNA targets suggests that these tiny RNA molecules likely act as molecular switches in the extensive regulatory web that involves thousands of transcripts. Most importantly, accumulating evidence suggests that numerous microRNAs are aberrantly expressed in human cancers. In this review, we discuss the emergent roles of microRNAs as switches that function to turn on/off known cellular microcircuits. We outline recent compelling evidence that deregulated microRNAmediated control of cellular microcircuits cooperates with other well-established regulatory mechanisms to confer the hallmark traits of the cancer cell. Furthermore, these exciting insights into aberrant microRNA control in cancer-associated circuits may be exploited for cancer therapies that will target deregulated miRNA switches.

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“…BART miRNAs are expressed at higher levels in epithelial malignancies than in lymphomas (21)(22)(23)(24). Several BART miRNAs have been shown to regulate cellular pathways and EBV latency.…”

mentioning

confidence: 99%

Epstein-Barr Virus MicroRNA miR-BART20-5p Suppresses Lytic Induction by Inhibiting BAD -Mediated caspase-3 -Dependent Apoptosis

Kim

Choi

Lee

2016

J Virol

Self Cite

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Epstein-Barr virus (EBV) is a human gammaherpesvirus associated with a variety of tumor types. EBV can establish latency or undergo lytic replication in host cells. In general, EBV remains latent in tumors and expresses a limited repertoire of latent proteins to avoid host immune surveillance. When the lytic cycle is triggered by some as-yet-unknown form of stimulation, lytic gene expression and progeny virus production commence. Thus far, the exact mechanism of EBV latency maintenance and the in vivo triggering signal for lytic induction have yet to be elucidated. Previously, we have shown that the EBV microRNA miR-BART20-5p directly targets the immediate early genes BRLF1 and BZLF1 as well as Bcl-2-associated death promoter (BAD) in EBV-associated gastric carcinoma. In this study, we found that both mRNA and protein levels of BRLF1 and BZLF1 were suppressed in cells following BAD knockdown and increased after BAD overexpression. Progeny virus production was also downregulated by specific knockdown of BAD. Our results demonstrated that caspase-3-dependent apoptosis is a prerequisite for BAD-mediated EBV lytic cycle induction. Therefore, our data suggest that miR-BART20-5p plays an important role in latency maintenance and tumor persistence of EBV-associated gastric carcinoma by inhibiting BAD-mediated caspase-3-dependent apoptosis, which would trigger immediate early gene expression. IMPORTANCEEBV has an ability to remain latent in host cells, including EBV-associated tumor cells hiding from immune surveillance. However, the exact molecular mechanisms of EBV latency maintenance remain poorly understood. Here, we demonstrated that miR-BART20-5p inhibited the expression of EBV immediate early genes indirectly, by suppressing BAD-induced caspase-3-dependent apoptosis, in addition to directly, as we previously reported. Our study suggests that EBV-associated tumor cells might endure apoptotic stress to some extent and remain latent with the aid of miR-BART20-5p. Blocking the expression or function of BART20-5p may expedite EBV-associated tumor cell death via immune attack and apoptosis.

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Expression of Viral MicroRNAs in Epstein-Barr Virus-Associated Gastric Carcinoma

Cited by 147 publications

References 22 publications

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells

Emerging roles of microRNAs as molecular switches in the integrated circuit of the cancer cell

Epstein-Barr Virus MicroRNA miR-BART20-5p Suppresses Lytic Induction by Inhibiting BAD -Mediated caspase-3 -Dependent Apoptosis

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Expression of Viral MicroRNAs in Epstein-Barr Virus-Associated Gastric Carcinoma

Cited by 147 publications

References 22 publications

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 + T cells

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 + T cells

Emerging roles of microRNAs as molecular switches in the integrated circuit of the cancer cell

Epstein-Barr Virus MicroRNA miR-BART20-5p Suppresses Lytic Induction by Inhibiting BAD -Mediated caspase-3 -Dependent Apoptosis

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Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells