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Review
. 2018 Aug 2:8:265.
doi: 10.3389/fonc.2018.00265. eCollection 2018.

Epstein-Barr Virus-Associated Malignancies: Roles of Viral Oncoproteins in Carcinogenesis

Affiliations
Review

Epstein-Barr Virus-Associated Malignancies: Roles of Viral Oncoproteins in Carcinogenesis

Ahmed El-Sharkawy et al. Front Oncol. .

Abstract

The Epstein-Barr virus (EBV) is the first herpesvirus identified to be associated with human cancers known to infect the majority of the world population. EBV-associated malignancies are associated with a latent form of infection, and several of the EBV-encoded latent proteins are known to mediate cellular transformation. These include six nuclear antigens and three latent membrane proteins (LMPs). In lymphoid and epithelial tumors, viral latent gene expressions have distinct pattern. In both primary and metastatic tumors, the constant expression of latent membrane protein 2A (LMP2A) at the RNA level suggests that this protein is the key player in the EBV-associated tumorigenesis. While LMP2A contributing to the malignant transformation possibly by cooperating with the aberrant host genome. This can be done in part by dysregulating signaling pathways at multiple points, notably in the cell cycle and apoptotic pathways. Recent studies also have confirmed that LMP1 and LMP2 contribute to carcinoma progression and that this may reflect the combined effects of these proteins on activation of multiple signaling pathways. This review article aims to investigate the aforementioned EBV-encoded proteins that reveal established roles in tumor formation, with a greater emphasis on the oncogenic LMPs (LMP1 and LMP2A) and their roles in dysregulating signaling pathways. It also aims to provide a quick look on the six members of the EBV nuclear antigens and their roles in dysregulating apoptosis.

Keywords: B-cells lymphoma; Burkitt’s lymphoma; Hodgkin’s lymphoma; nasopharyngeal carcinoma; non-Hodgkin’s lymphoma; oncogenes; oncoproteins.

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Figures

Figure 1
Figure 1
Epstein–Barr virus (EBV)-associated malignancies patterns of gene expression. Latency III EBV gene expression: found in in vitro transformed B cells into lymphoblastoid cell lines (LCLs); Latency I EBV gene expression: found in the majority (85%) of EBV-positive Burkitt lymphomas (BLs); Wp-restricted Latency: found in a minority (15%) of EBV-positive BLs (Wp-BL); and Latency II EBV gene expression: found in EBV-positive Hodgkin lymphoma (HL) as well as the EBV-associated epithelial malignancies, nasopharyngeal carcinoma (NPC), and gastric carcinoma (GC). Latent proteins [Epstein–Barr virus nuclear antigen (EBNA)1, EBNA2, EBNA3A, EBNA3B, EBNA3C, EBNA-LP, BHRF1, latent membrane protein (LMP)1 and LMP2A/B] are shown in blue. Non-coding RNAs [Epstein–Barr encoded RNAs (EBERs), miR-BHRF1s, and miR-BamHI A rightward transcripts (BARTs)] are shown in red, and selected latent promoters (Cp, Wp, and Qp) are shown in green. Connecting lines denote splicing patterns, while blocks indicate exons. In Wp-BL, EBNA-LP is truncated due to a genomic deletion and is therefore denoted as t-EBNA-LP (14).
Figure 2
Figure 2
Latent membrane proteins (LMPs) (1 and 2A) downstream signal transduction pathways (28).
Figure 3
Figure 3
Molecular interactions and signaling pathways engaged by LMP1 in the carcinogenesis of nasopharyngeal carcinomas (NPCs). LMP1 C-terminal activation region 1 (CTAR1) regulates NIK/IKKs activation and then phosphorylates IκBα, thus activating NF-κB through TNFR-associated factor (TRAF)1, TRAF2, and TRAF3; while CTAR2 activates NF-κB through tumor necrosis factor receptor-associated death domain (TRADD) and TRAF2. Active NF-κB induces the cell immortalization via the upregulation of the telomerase activity through the translocation of hTERT protein bound to NF-κB, blocks the cell apoptosis via the upregulation of the survivin activity, and promotes the cell proliferation via regulating survivin, CyclinD1, CyclinE and EGFR signaling, etc. Also, LMP1 can increase the serine phosphorylation level of Annexin A2 by activating the PKC signaling pathway, which can promote the cell proliferation. LMP1 CTAR2 triggers AP-1 signaling cascade by activating ERK, P38, and the c-Jun N-terminal kinases (JNKs), members of the stress-activated group of MAP kinases, via the binding with TRADD/TRAF2 complex. Active AP-1 upregulates the expression of MMP9 and mediates invasion and metastasis of NPC cells. LMP1 CTAR3 between CTAR1 and CTAR2 triggers the Janus kinase (JAK3)/signal transducers and activators of transcription (STAT) signaling pathway, which can enhance VEGF transcription and expression, thereby promoting invasion and metastasis of NPC cells (42).
Figure 4
Figure 4
LMP1-mediated activation of nuclear factor kB pathway (43).
Figure 5
Figure 5
Epstein–Barr virus (EBV)–LMP1 regulates T/S/Z-induced necroptosis. EBV–LMP1 (−) cells stimulated with T/S/Z undergo necroptosis through RIPK1–RIPK3 signaling. However, EBV–LMP1 (+) cells can survive under this stimulation. On the one hand, LMP1 interacts directly with both RIPK1 and RIPK3 through its C-terminal activation region. On the one hand, LMP1 promotes K63-linked polyubiquitination of RIPK1 and suppresses the protein expression while inhibiting K63-linked polyubiquitination of RIPK3. These effects contribute to the activation of NF-κB and disruption of necrosome formation, collectively switching cell fate from death to survival (63).
Figure 6
Figure 6
A schematic diagram showing the signaling pathways engaged by the LMP2A gene. The N terminal domain of LMP2A prevents B cell receptor (BCR) signaling by recruiting Nedd4-like ubiquitin-protein ligases and B-cell signaling molecules, leading to the degradation of LMP2A and its associated molecules in a ubiquitin-dependent manner. LMP2A also provides a survival signal to BCR-negative B-cells through the activation of the Ras/phosphotidylinositol 3-kinase (PI3-K)/Akt pathway. Activating this pathway induces the transcription of anti-apototic genes, the expression of which is controlled by NF-κ B. Notch signaling regulates various cellular processes including cell survival and proliferation. In LMP2A-expressing splenic B cells, Notch activation is reported. Notch signaling is closely related to the pathogenesis of Hodgkin lymphoma (HL). LMP2A perturbs the turnover of β-catenin and other proteins that are involved in Wnt signaling. β-catenin is stabilized and activated by LMP2A through PI3-K/Akt activation, which inhibits glycogen synthase kinase-3β (GSK-3β). The association of LMP2A with mitogen-activated protein kinase (MAPK) was implicated in the development of B-cell malignancy while the activation of MAPK was not observed in LMP2A-expressing epithelial cells. The multiple cysteine motifs within the C-terminal of LMP2A are required for LMP2A palmitoylation. Studies of the proposed palmitoylation are required for LMP2A-mediated survival signal and function as they regulate the protein interaction or localization required for LMP2A-mediated cell survival.

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