Abstract
BackgroundThe Epstein-Barr virus (EBV) is closely associated with several types of malignancies. EBV is normally present in the latent state in the peripheral blood B cell compartment. The EBV latent-to-lytic switch is required for virus spread and virus-induced carinogenesis. Immunosuppression or DNA damage can induce the reactivation of EBV replication. EBV alone is rarely sufficient to cause cancer. In this study, we investigated the roles of host microRNAs and environmental factors, such as DNA-damage agents, in EBV reactivation and its association with lymphomagenesis.MethodsWe first analyzed the publicly available microRNA array data containing 45 diffuse large B-cell lymphoma patients and 10 control lymph nodes or B cells with or without EBV infection. In situ hybridization for miR-18a and immunohistochemitry were performed to evaluate the correlation between the expression of miR-18a and nuclear EBV protein EBNA1 in lymphoid neoplasm. The proliferative effects of miR-18a were investigated in EBV-positive or –negative lymphoid neoplasm cell lines. EBV viral load was measured by a quantitative real-time EBV PCR and FISH assay. The genomic instability was evaluated by CGH-array.ResultsIn this study, we analyzed the publicly available microRNA array data and observed that the expression of the miR-17-92 cluster was associated with EBV status. In situ hybridization for miR-18a, which is a member of the miR-17-92 cluster, showed a significant upregulation in lymphoma samples. miR-18a, which shares the homolog sequence with EBV-encoded BART-5, promoted the proliferation of lymphoma cells in an EBV status-dependent manner. The DNA-damaging agent UV or hypoxia stress induced EBV activation, and miR-18a contributed to DNA damaging-induced EBV reactivation. In contrast to the promoting effect of ATM on the lytic EBV reactivation in normoxia, ATM inhibited lytic EBV gene expression and decreased the EBV viral load in the prescence of hypoxia-induced DNA damage. miR-18a reactivated EBV through inhibiting the ATM-mediated DNA damage response (DDR) and caused genomic instability.ConclusionsTaken together, these results indicate that DNA-damaging agents and host microRNAs play roles in EBV reactivation. Our study supported the interplay between host cell DDR, environmental genotoxic stress and EBV.
Highlights
The Epstein-Barr virus (EBV) is closely associated with several types of malignancies
Increased expression of miR-18a in lymphomas patients is associated with EBV infection and a shorter survival We first investigated the expressions of miR-18a and the miR-17-92 cluster in lymphomas samples and the association with EBV infection
The unsupervised hierarchical clustering of microRNA expression showed that EBV-infected B cells had upregulated miR-17-92 cluster expression and were clustered together (Fig. 1b), indicating that the expression of the miR-17-92 cluster was correlated with the EBV infection status. miR-18a, which shares sequences with EBV-Micro RNA (miRNA)-BART5, was upregulated in EBV-infected B cells; EBV-miRNA-BART5 did not show upregulated expression in EBV-positive B cells. miR-155, which can be altered by EBV infection, was notably upregulated. miR-29a/b/c, which share sequences with EBV miRNA BART1-3p were downregulated
Summary
The Epstein-Barr virus (EBV) is closely associated with several types of malignancies. EBV is normally present in the latent state in the peripheral blood B cell compartment. The EBV latent-to-lytic switch is required for virus spread and virus-induced carinogenesis. Immunosuppression or DNA damage can induce the reactivation of EBV replication. We investigated the roles of host microRNAs and environmental factors, such as DNA-damage agents, in EBV reactivation and its association with lymphomagenesis. Reactivation of the viral replication plays an important role in the development of EBV-associated malignancy. Except for hematological malignancies, the lytic form of EBV infection was observed in malignant breast epithelial cells in certain cases of breast cancer [8]. EBV reactivation-induced cell proliferation and migration caused the relapse of NPC [9]. Elevated levels of EBV DNA is observed in EBV-positive lymphoma patients with active disease but not in EBV-positive patients in remission or those with EBV-negative tumors, indicating that the EBV viral load at lymphoma diagnosis is an indicator of disease activity and biological characteristics associated with a negative prognosis [10]
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