Virus-encoded microRNA contributes to the molecular profile of EBV-positive Burkitt lymphomas

Piccaluga, Pier Paolo; Navari, Mohsen; Falco, Giulia De; Ambrosio, Maria Raffaella; Lazzi, Stefano; Fuligni, Fabio; Bellan, Cristiana; Rossi, Mosè; Sapienza, Maria Rosaria; Laginestra, Maria Antonella; Etebari, Maryam; Rogena, Emily; Tumwine, Lynnette K; Tripodo, Claudio; Gibellini, Davide; Consiglio, Jessica; Croce, Carlo M.; Pileri, Stefano; Leoncini, Lorenzo

doi:10.18632/oncotarget.4399

Cited by 41 publications

(25 citation statements)

References 65 publications

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“…Our observation that eBL tumors express varying levels of EBV miRNAs suggested a role for EBV non-coding transcripts in eBL disease progression, as postulated by another group (Piccaluga et al, 2016). The BHRF1 miRNA cluster has been shown to strongly potentiate the transforming properties of EBV (Li et al, 2012; Ma et al, 2016), and have been shown to downregulate genes that antagonize or prevent B cell growth (Bernhardt et al, 2016).…”

Section: Discussionsupporting

confidence: 79%

“…More recently, it has been discovered that the virus expresses numerous viral miRNAs that function to maintain the virus through the subversion of the immune system and protection from apoptosis (Seto et al, 2010; Navari et al, 2014). It has also been demonstrated that EBV miRNAs are also significant viral contributors to the continued survival and proliferation of BL cells where viral loss leading to apoptosis could be compensated by expression of ebv-miR-BHRF1 subset (Vereide et al, 2014; Piccaluga et al, 2016). Combined, these viral miRNA effects may have the potential to worsen prognosis and response to treatment but have yet to be characterized vis-à-vis eBL survival studies and other clinical features.…”

Section: Introductionmentioning

confidence: 99%

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Human and Epstein-Barr Virus miRNA Profiling as Predictive Biomarkers for Endemic Burkitt Lymphoma

et al. 2017

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Endemic Burkitt lymphoma (eBL) is an aggressive B cell lymphoma and is associated with Epstein-Barr virus (EBV) and Plasmodium falciparum malaria co-infections. Central to BL oncogenesis is the over-expression of the MYC proto-oncogene which is caused by a translocation of an Ig enhancer in approximation to the myc gene. While whole genome/transcriptome sequencing methods have been used to define driver mutations and transcriptional dysregulation, microRNA (miRNA) dysregulation and differential expression has yet to be fully characterized. We hypothesized that both human and EBV miRNAs contribute to eBL clinical presentation, disease progression, and poor outcomes. Using sensitive and precise deep sequencing, we identified miRNAs from 17 Kenyan eBL patient tumor samples and delineated the complement of both host and EBV miRNAs. One human miRNA, hsa-miR-10a-5p was found to be differentially expressed (DE), being down-regulated in jaw tumors relative to abdominal and in non-survivors compared to survivors. We also examined EBV miRNAs, which made up 2.7% of the miRNA composition in the eBL samples. However, we did not find any significant associations regarding initial patient outcome or anatomical presentation. Gene ontology analysis and pathway enrichment of previously validated targets of miR-10a-5p suggest that it can promote tumor cell survival as well as aid in evasion of apoptosis. To examine miR-10a-5p regulatory effect on gene expression in eBL, we performed a pairwise correlation coefficient analysis on the expression levels of all its validated targets. We found a significant enrichment of correlated target genes consistent with miR-10a-5p impacting expression. The functions of genes and their correlation fit with multiple target genes impacting tumor resilience. The observed downregulation of miR-10a and associated genes suggests a role for miRNA in eBL patient outcomes and has potential as a predictive biomarker that warrants further investigation.

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Human and Epstein-Barr Virus miRNA Profiling as Predictive Biomarkers for Endemic Burkitt Lymphoma

et al. 2017

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“…To clarify the roles of cellular and EBV-encoded mi-RNAs in vivo, it is important to determine the expression profile of total miRNAs in primary tumors of EBVassociated lymphoma. To date, the expression profiles of EBV-encoded miRNAs have been investigated in primary NPC, nasal NK/T-cell lymphoma, gastric cancer samples, and LCLs using real-time RT-PCR [10,11,14,[30][31][32][33][34][35][36][37], but there is little information about EBV-encoded miRNA expression in primary tumors of EBV-associated B-cell lymphoma. Next-generation sequencing (NGS) is a powerful tool for investigating the expression of small RNAs, including cellular and viral miRNAs.…”

Section: Introductionmentioning

confidence: 99%

Next‐generation sequencing of miRNAs in clinical samples of Epstein–Barr virus‐associated B‐cell lymphomas

et al. 2017

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Epstein–Barr virus (EBV) encodes 49 microRNAs (miRNAs) in the BART and BHRF1 regions of its genome. Although expression profiles of EBV‐encoded miRNAs have been reported for EBV‐positive cell lines and nasopharyngeal carcinoma, to date there is little information about total miRNA expression, including cellular and viral miRNAs, in the primary tumors of EBV‐associated B‐lymphoproliferative disorders. In this study, next‐generation sequencing and quantitative real‐time reverse transcription‐PCR were used to determine the expression profiles of miRNAs in EBV‐infected cell lines and EBV‐associated B‐cell lymphomas, including AIDS‐related diffuse large B‐cell lymphoma (DLBCL), pyothorax‐associated lymphoma, methotrexate‐associated lymphoproliferative disorder, EBV‐positive DLBCL of the elderly, and Hodgkin lymphoma. Next‐generation sequencing revealed that EBV‐encoded miRNAs accounted for up to 34% of total annotated miRNAs in these cases. Expression of three miR‐BHRF1s was significantly higher in AIDS‐related DLBCL and pyothorax‐associated lymphoma compared with methotrexate‐associated lymphoproliferative disorder and EBV‐positive DLBCL of the elderly, suggesting the association of miR‐BHRF1s expression with latency III EBV infection. Heat map/clustering analysis of expression of all miRNAs, including cellular and EBV miRNAs, by next‐generation sequencing demonstrated that each EBV tumor, except methotrexate‐associated lymphoproliferative disorder, formed an isolated cluster. Principal component analysis based on the EBV‐encoded miRNA expression showed that each EBV tumor formed a distinguished cluster, but AIDS‐related DLBCL and pyothorax‐associated lymphoma formed larger clusters than other tumors. These data suggest that expression of miRNAs, including EBV‐encoded miRNAs, is associated with the tumor type and status of virus infection in these tumors.

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“… 13 They were reported to promote viral latency or cancer development by targeting both viral and cellular genes. 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 …”

mentioning

confidence: 99%

Epstein-Barr virus-encoded miR-BART6-3p inhibits cancer cell metastasis and invasion by targeting long non-coding RNA LOC553103

et al. 2016

Cell Death Dis

127

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Epstein-Barr virus (EBV) infection is causatively related to a variety of human cancers, including nasopharyngeal carcinoma (NPC) and gastric cancer (GC). EBV encodes 44 mature miRNAs, a number of which have been proven to promote carcinogenesis by targeting host genes or self-viral genes. However, in this study, we found that an EBV-encoded microRNA, termed EBV-miR-BART6-3p, inhibited EBV-associated cancer cell migration and invasion including NPC and GC by reversing the epithelial–mesenchymal transition (EMT) process. Using microarray analysis, we identified and validated that a novel long non-coding RNA (lncRNA) LOC553103 was downregulated by EBV-miR-BART6-3p, and LOC553103 knockdown by specific siRNAs phenocopied the effect of EBV-miR-BART6-3p, while LOC553103 overexpression promoted cancer cell migration and invasion to facilitate EMT. In conclusion, we determined that EBV-miR-BART6-3p, a microRNA encoded by oncogenic EBV, inhibited EBV-associated cancer cell migration and invasion by targeting and downregulating a novel lncRNA LOC553103. Thus, our study presents an unreported mechanism underlying EBV infection in EBV-associated cancer carcinogenesis, and provides a potential novel diagnosis and treatment biomarker for NPC and other EBV-related cancers.

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Virus-encoded microRNA contributes to the molecular profile of EBV-positive Burkitt lymphomas

Cited by 41 publications

References 65 publications

Human and Epstein-Barr Virus miRNA Profiling as Predictive Biomarkers for Endemic Burkitt Lymphoma

Human and Epstein-Barr Virus miRNA Profiling as Predictive Biomarkers for Endemic Burkitt Lymphoma

Next‐generation sequencing of miRNAs in clinical samples of Epstein–Barr virus‐associated B‐cell lymphomas

Epstein-Barr virus-encoded miR-BART6-3p inhibits cancer cell metastasis and invasion by targeting long non-coding RNA LOC553103

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