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EBV induces persistent NF-?B activation and contributes to survival of EBV-positive neoplastic T- or NK-cells.

ABSTRACT: Epstein-Barr virus (EBV) has been detected in several T- and NK-cell neoplasms such as extranodal NK/T-cell lymphoma nasal type, aggressive NK-cell leukemia, EBV-positive peripheral T-cell lymphoma, systemic EBV-positive T-cell lymphoma of childhood, and chronic active EBV infection (CAEBV). However, how this virus contributes to lymphomagenesis in T or NK cells remains largely unknown. Here, we examined NF-?B activation in EBV-positive T or NK cell lines, SNT8, SNT15, SNT16, SNK6, and primary EBV-positive and clonally proliferating T/NK cells obtained from the peripheral blood of patients with CAEBV. Western blotting, electrophoretic mobility shift assays, and immunofluorescent staining revealed persistent NF-?B activation in EBV-infected cell lines and primary cells from patients. Furthermore, we investigated the role of EBV in infected T cells. We performed an in vitro infection assay using MOLT4 cells infected with EBV. The infection directly induced NF-?B activation, promoted survival, and inhibited etoposide-induced apoptosis in MOLT4 cells. The luciferase assay suggested that LMP1 mediated NF-?B activation in MOLT4 cells. IMD-0354, a specific inhibitor of NF-?B that suppresses NF-?B activation in cell lines, inhibited cell survival and induced apoptosis. These results indicate that EBV induces NF-?B-mediated survival signals in T and NK cells, and therefore, may contribute to the lymphomagenesis of these cells.

SUBMITTER: Takada H

PROVIDER: S-EPMC5367708 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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EBV induces persistent NF-κB activation and contributes to survival of EBV-positive neoplastic T- or NK-cells.

Takada Honami H Imadome Ken-Ichi KI Shibayama Haruna H Yoshimori Mayumi M Wang Ludan L Saitoh Yasunori Y Uota Shin S Yamaoka Shoji S Koyama Takatoshi T Shimizu Norio N Yamamoto Kouhei K Fujiwara Shigeyoshi S Miura Osamu O Arai Ayako A

PloS one 20170327 3

Epstein-Barr virus (EBV) has been detected in several T- and NK-cell neoplasms such as extranodal NK/T-cell lymphoma nasal type, aggressive NK-cell leukemia, EBV-positive peripheral T-cell lymphoma, systemic EBV-positive T-cell lymphoma of childhood, and chronic active EBV infection (CAEBV). However, how this virus contributes to lymphomagenesis in T or NK cells remains largely unknown. Here, we examined NF-κB activation in EBV-positive T or NK cell lines, SNT8, SNT15, SNT16, SNK6, and primary E ...[more]

PMID: 28346502

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Project description:BackgroundEpstein-Barr virus (EBV) is ubiquitously associated with nasopharyngeal carcinoma (NPC). EBV encodes two groups of microRNAs (miRNAs) which are divided into BamHI fragment H rightward open reading frame 1 (BHRF1) and BamHI-A rightward transcripts (BART) microRNAs. EBV miR-BART has been found to be involved in the development and progression of NPC. However, so far the role of EBV-miR-BART8-3p in NPC progression remains unknown. This study aimed to investigate the role of EBV-miR-BART8-3p in NPC and explore the underlying mechanisms.MethodsmiRNA expression was profiled in NPC and normal nasopharyngeal mucosal specimens using miRNA sequencing. EBV-miR-BART8-3p and RNF38 expression was quantified with qPCR assay. The migration, invasion and metastasis of NPC cells were evaluated using CCK-8, colony-forming, wound-healing, and migration and invasion assays. The expression levels of epithelial-mesenchymal transition (EMT)-related markers,metastasis-related markers and NF-κB and Erk1/2 signaling proteins were determined using Western blotting. Tumorigenic assay was performed to evaluate the pulmonary metastatic ability of NPC cells in vivo.ResultsEBV BART miRNAs were highly over-expressed and co-expressed in NPC and might be associated with deactivated immune response in NPC according to the sequencing analysis. EBV-miR-BART8-3p expression was significantly higher in human NPC specimens than in normal nasopharyngeal mucosal specimens. EBV-miR-BART8-3p was found to promote NPC migration, invasion and metastasis, drove an EMT process and upregulated expression of metastasis-related proteins expression in NPC cells. Our data showed EBV-miR-BART8-3p directly targeted RNF38 in NPC cells.ConclusionThe present study demonstrates that EBV-miR-BART8-3p plays a significant role in inducing EMT and promoting metastasis through directly targeting RNF38 in NPC cells via the activation of NF-κB and Erk1/2 signaling pathways. Our findings suggest that EBV-miR-BART8-3p is a potential therapeutic target for NPC.

Dataset Information

EBV induces persistent NF-?B activation and contributes to survival of EBV-positive neoplastic T- or NK-cells.

Publications

EBV induces persistent NF-κB activation and contributes to survival of EBV-positive neoplastic T- or NK-cells.

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