Targeting of <scp>DICE1</scp> tumor suppressor by Epstein–Barr virus‐encoded miR‐BART3* microRNA in nasopharyngeal carcinoma

Lei, Ting; Yuen, Kit‐San; Xu, Rui; Tsao, Sai Wah; Chen, Honglin; Li, Mengfeng; Kok, Kin‐Hang; Jin, Dong-Yan

doi:10.1002/ijc.28007

Cited by 94 publications

(69 citation statements)

References 44 publications

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“…As shown in Fig 3, the 3’UTRs of the cellular mRNAs encoding DICE1, a proposed target for miR-BART3 [23], Dicer, a proposed target for miR-BART6 [31], and TOMM22, a proposed target for miR-BART16 [32], all produced a readily detectable inhibitory effect on FLuc expression when present in cis in cells expressing the cognate miR-BART miRNA. In contrast, we did not see a significant reduction mediated by the 3’UTR of STAT1, a proposed target for miR-BART8 [33], or by the 3’UTR of caspase 3 (CASP3), a proposed target for miR-BART16 [14].…”

Section: Resultsmentioning

confidence: 99%

EBV BART MicroRNAs Target Multiple Pro-apoptotic Cellular Genes to Promote Epithelial Cell Survival

2015

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Epstein-Barr virus (EBV) is a ubiquitous human γ-herpesvirus that can give rise to cancers of both B-cell and epithelial cell origin. In EBV-induced cancers of epithelial origin, including nasopharyngeal carcinomas (NPCs) and gastric carcinomas, the latent EBV genome expresses very high levels of a cluster of 22 viral pre-miRNAs, called the miR-BARTs, and these have previously been shown to confer a degree of resistance to pro-apoptotic drugs. Here, we present an analysis of the ability of individual miR-BART pre-miRNAs to confer an anti-apoptotic phenotype and report that five of the 22 miR-BARTs demonstrate this ability. We next used photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) to globally identify the mRNA targets bound by these miR-BARTs in latently infected epithelial cells. This led to the identification of ten mRNAs encoding pro-apoptotic mRNA targets, all of which could be confirmed as valid targets for the five anti-apoptotic miR-BARTs by indicator assays and by demonstrating that ectopic expression of physiological levels of the relevant miR-BART in the epithelial cell line AGS resulted in a significant repression of the target mRNA as well as the encoded protein product. Using RNA interference, we further demonstrated that knockdown of at least seven of these cellular miR-BART target transcripts phenocopies the anti-apoptotic activity seen upon expression of the relevant EBV miR-BART miRNA. Together, these observations validate previously published reports arguing that the miR-BARTs can exert an anti-apoptotic effect in EBV-infected epithelial cells and provide a mechanistic explanation for this activity. Moreover, these results identify and validate a substantial number of novel mRNA targets for the anti-apoptotic miR-BARTs.

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Section: Resultsmentioning

confidence: 99%

EBV BART MicroRNAs Target Multiple Pro-apoptotic Cellular Genes to Promote Epithelial Cell Survival

2015

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“…31 EBV-MiR-BART3* overcomes the growth suppressive activity of DICE1 and stimulates cell proliferation. 26 EBV-miR-BART1 is probably involved in the regulation of metabolism genes. 35 EBVmiR-BART7 has been recently reported to be detectable in NPC patient plasma samples and enhance the in vitro proliferation and migration of NPC cells.…”

Section: Discussionmentioning

confidence: 99%

“…This virus expresses more than 40 mature miRNAs in latently infected cells. Of them, some miRNAs encoded by BamH I-A rightward transcripts (BARTs) of EBV are disclosed to be highly expressed in some cancers such as gastric cancer, 23 lymphomas 24 and NPC, [25][26][27] contributing to viral latency, [28][29][30] host cell survival, 30,31 immune escape, 32 cell proliferation, 33 cell apoptosis 31,34 and cancer metabolism. 35 However, there have been few reports of the relationship between viral miRNAs and EMT in cancer to date.…”

Section: Introductionmentioning

confidence: 99%

EBV-miR-BART7-3p promotes the EMT and metastasis of nasopharyngeal carcinoma cells by suppressing the tumor suppressor PTEN

et al. 2014

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The epithelial-mesenchymal transition (EMT) is crucial to cancer progression and metastasis. Although multiple cellular miRNAs have been identified to regulate the EMT and metastasis in cancers, the role of viral miRNAs in cancer progression remains largely unknown. Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated malignancy typically characterized by its early metastasis. In the present study, we have discovered the involvement of a viral miRNA, EBV-miR-BART7-3p, in the EMT and metastasis of NPC cells. Initially, we observed that EBV-miR-BART7-3p was highly expressed in NPC and positively correlated with lymph node metastasis and clinical stage of NPC. Subsequently, we demonstrated that EBV-miR-BART7-3p enhanced cell migration/invasion in vitro, cancer metastasis in vivo, and particularly the EMT characterized by loss of epithelial markers and gain of mesenchymal features in NPC cells. Furthermore, mechanistic studies disclosed that EBV-miR-BART7-3p targeted a major human tumor suppressor PTEN, modulating PI3K/Akt/GSK-3β signaling and eventually leading to the high expression and nuclear accumulation of Snail and β-catenin, which favor EMT. Knockdown of PTEN could phenocopy the effect of EBV-miR-BART7-3p, whereas re-expression of PTEN resulted in a phenotypic reversion. Moreover, these findings were supported by an observation of an EBV-positive cell model in which silencing of endogenous EBV-miR-BART7-3p partially attenuated cell migration/invasion and altered EMT protein expression pattern via reverting PI3K/Akt, Snail and β-catenin expression. Thus, this study suggests a novel mechanism by which EBV-miR-BART7-3p modulates the EMT and metastasis of NPC cells, and a clinical implication of EBV-miR-BART7-3p as a potential biomarker or therapeutic target.

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“…1 One important consequence of EBV infection is malignant transformation of epithelial cells, promoted by EBV-encoded protein and microRNAs. [26][27][28][29] Another is EBV-induced inflammatory cytokines in the tumor microenvironment, resulting in angiogenesis and metastasis. 8 As a key component of innate immunity, LF has vital roles in host defense against infection and excessive inflammation.…”

Section: Lf Expression Levels Correlated Inversely With Mcp-1 and Il-mentioning

confidence: 99%

Lactoferrin suppresses the Epstein–Barr virus-induced inflammatory response by interfering with pattern recognition of TLR2 and TLR9

Zheng

Qin²,

Ye³

et al. 2014

Laboratory Investigation

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Epstein-Barr virus (EBV) infection contributes to tumorigenesis of various human malignancies including nasopharyngeal carcinoma (NPC). EBV triggers innate immune and inflammatory responses partly through Toll-like receptor (TLR) signaling. Lactoferrin (LF), with its anti-inflammatory properties, is an important component of the innate immune system. We previously reported that LF protects human B lymphocytes from EBV infection by its ability to bind to the EBV receptor CD21, but whether LF can suppress EBV-induced inflammation is unclear. Here, we report that LF reduced synthesis of IL-8 and monocyte chemoattractant protein-1 (MCP-1) induced by EBV in macrophages via its suppression of NF-kB activity. LF interacted with TLR2 and interfered with EBV-triggered TLR2-NF-kB activation. LF inhibited the ability of TLR9 to recognize dsDNA by binding to its co-receptor CD14, which blocked the interaction between CD14 and TLR9. EBV-induced inflammation was thus aggravated in the presence of CD14. In addition, LF expression levels were significantly downregulated in NPC specimens, and correlated inversely with IL-8 and MCP-1 expression. These findings suggest that LF may suppress the EBV-induced inflammatory response through interfering with the activation of TLR2 and TLR9.

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Targeting of DICE1 tumor suppressor by Epstein–Barr virus‐encoded miR‐BART3* microRNA in nasopharyngeal carcinoma

Cited by 94 publications

References 44 publications

EBV BART MicroRNAs Target Multiple Pro-apoptotic Cellular Genes to Promote Epithelial Cell Survival

EBV BART MicroRNAs Target Multiple Pro-apoptotic Cellular Genes to Promote Epithelial Cell Survival

EBV-miR-BART7-3p promotes the EMT and metastasis of nasopharyngeal carcinoma cells by suppressing the tumor suppressor PTEN

Lactoferrin suppresses the Epstein–Barr virus-induced inflammatory response by interfering with pattern recognition of TLR2 and TLR9

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