Epstein–Barr virus-encoded microRNA BART1 induces tumour metastasis by regulating PTEN-dependent pathways in nasopharyngeal carcinoma

Cai, Longmei; Ye, Yanfen; Jiang, Qiang; Chen, Yuxiang; Lyu, Xiaoming; Li, Jinbang; Wang, Shuang; Liu, Tengfei; Cai, Hongwei; Yao, Kai-Tai; Li, Jiliang; Li, Xin

doi:10.1038/ncomms8353

Cited by 183 publications

(173 citation statements)

References 65 publications

(82 reference statements)

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“…EBV miR-BART1-5p and BART1-3p are dramatically increased in the N2-3 stages or advanced stages (III-IV) of NPC (Cai et al, 2015;Zheng et al, 2016). The levels of both miR-BART7 and miR-BART13 in NPC plasma are found to be present at distinct levels among patients with different stages of NPC, with elevated levels among patients with advanced disease.…”

Section: Ebv-encoded and Ebv-dysregulated Mirnas Are Potential Biomarmentioning

confidence: 84%

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-encoded and Ebv-dysregulated Mirnas Are Potential Biomarmentioning

confidence: 84%

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

Zuo

Yue

et al. 2017

Virol. Sin.

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“…Interestingly, recent investigations of potential EBV microRNA target genes revealed an inhibition of PTEN and extensive deregulation of several pathways involved in NPC. We previously reported that alteration of EBV-miR-BART1 and EBV-miR-BART7 expression results in migration and invasion of NPC cells through directly targeting tumour suppressor PTEN [29, 30]. Therefore, it suggests a possibility that aberrant CpG island methylation of PTEN confers “the second or additional hit” in NPC cells that contain EBV encoded microRNAs targeting this gene.…”

Section: Discussionmentioning

confidence: 99%

Higher methylation intensity induced by EBV LMP1 via NF-κB/DNMT3b signaling contributes to silencing of PTEN gene

et al. 2016

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Phosphatase and tensin homolog (PTEN) is a major tumor suppressor and usually silenced via the deletion, insertion and mutation. We previously discovered its inactivation via aberrant CpG island methylation. Here, we provide further evidence that EBV latent membrane protein 1(LMP1) can induce a higher intensity of DNA methylation at PTEN CpG islands, inactivating PTEN at the cellular and molecular level. Initially, increased methylation intensity of PTEN CpG islands was observed in EBV-infected nasopharyngeal carcinoma (NPC) cells, accompanied by decreased PTEN expression. In NPC tissue samples showing the methylation at PTEN promoter, LMP1 was highly expressed in higher methylation intensity group relative to lower intensity group, and DNA methyltransferase 3b (DNMT3b) expression was positively correlated with LMP1 expression. Moreover, transfection of LMP1 gene into EBV-negative NPC cells demonstrated that LMP1 up-regulated DNMT3b expression, leading to a higher intensity of PTEN CpG island methylation. Mechanistically, computational prediction and luciferase reporter assay identified a functional NF-κB binding site on DNMT3b promoter and the mutated NF-κB binding site abolished LMP1-mediated DNMT3b activation. Chromatin immunoprecipitation displayed that NF-κB p65 subunit constitutively bound to DNMT3b promoter, supporting the activation of DNMT3b by EBV LMP1 via NF-κB signaling. Furthermore, the expression level of DNMT3b was observed to be increased in the nuclei of LMP1-expressing NPC cells, and a NF-κB inhibitor, PDTC, counteracted LMP1-mediated DNMT3b overexpression. Thus, this study first reports that LMP1-mediated NF-κB can up-regulate DNMT3b transcription, thereby leading to relatively higher methylation intensity at PTEN CpG islands, and ultimately silencing major tumor suppressor PTEN.

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“…Strikingly, among 24 upregulated miRNAs differently expressed between NPC and nonmalignant nasopharyngeal samples, Cai and coworkers found that EBV miR-BARTs were more than twice the number of endogenous human miRNAs (62.5% vs 29.2%, respectively) [76]. The upregulation of BART miRNAs was also reported in mice xenograft tumors produced from EBV-positive carcinoma cells C666-1 (nasopharyngeal) and AGS-BX1 (gastric), as well as the EBV-positive BL36 (Burkitt Lymphoma) [77].…”

Section: Ebv In Cancer Progression: Lmps and Ebnas Are Not The Wholementioning

confidence: 99%

Viral Carcinogenesis Beyond Malignant Transformation: EBV in the Progression of Human Cancers

Oliveira

Müller-Coan

Pagano

2016

Trends in Microbiology

104

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Cancer progression begins when malignant cells colonize adjacent sites, and it is characterized by increasing tumor heterogeneity, invasion and dissemination of cancer cells. Clinically, progression is the most relevant stage in the natural history of cancers. A given virus is usually regarded as oncogenic because of its ability to induce malignant transformation of cells. Nonetheless, oncogenic viruses may also be important for the progression of infection-associated cancers. Recently this hypothesis has been addressed because of studies on the contribution of the Epstein–Barr virus (EBV) to the aggressiveness of nasopharyngeal carcinoma (NPC). Several EBV products modulate cancer progression phenomena, such as the epithelial–mesenchymal transition, cell motility, invasiveness, angiogenesis, and metastasis. In this regard, there are compelling data about the effects of EBV latent membrane proteins (LMPs) and EBV nuclear antigens (EBNAs), as well as nontranslated viral RNAs, such as the EBV-encoded small nonpolyadenylated RNAs (EBERs) and viral microRNAs, notably EBV miR-BARTs. The available data on the mechanisms and players involved in the contribution of EBV infection to the aggressiveness of NPC are discussed in this review. Overall, this conceptual framework may be valuable for the understanding of the contribution of some infectious agents in the progression of cancers.

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Epstein–Barr virus-encoded microRNA BART1 induces tumour metastasis by regulating PTEN-dependent pathways in nasopharyngeal carcinoma

Cited by 183 publications

References 65 publications

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

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

Higher methylation intensity induced by EBV LMP1 via NF-κB/DNMT3b signaling contributes to silencing of PTEN gene

Viral Carcinogenesis Beyond Malignant Transformation: EBV in the Progression of Human Cancers

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