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New insights into Epstein‑Barr virus‑associated tumors: Exosomes (Review)

  • Authors:
    • Wei Chen
    • Yao Xie
    • Tingting Wang
    • Lin Wang
  • View Affiliations

  • Published online on: November 11, 2021
  • Article Number: 13
  • Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Epstein‑Barr virus (EBV) is endemic worldwide and is associated with a number of human tumors. EBV‑associated tumors have unique mechanisms of tumorigenesis. EBV encodes multiple oncogenic molecules that can be loaded into exosomes released by EBV+ tumor cells to mediate intercellular communication. Moreover, different EBV+ tumor cells secrete exosomes that act on various target cells with various biological functions. In addition to oncogenicity, EBV+ exosomes have potential immunosuppressive effects. Investigating EBV+ exosomes could identify the role of EBV in tumorigenesis and progression. The present review summarized advances in studies focusing on exosomes and the functions of EBV+ exosomes derived from different EBV‑associated tumors. EBV+ exosomes are expected to become a new biomarker for disease diagnosis and prognosis. Therefore, exosome‑targeted therapy displays potential.


Epstein-Barr virus (EBV), which was first discovered in 1964 (1), is endemic worldwide and is associated with a number of human tumors, including nasopharyngeal carcinoma (NPC), EBV-associated gastric cancer (EBVaGC) and certain types of lymphoma (24). Previous studies have demonstrated that EBV encodes multiple viral proteins and nucleic acids that have complex effects in suppressing tumor cell apoptosis promoting tumor angiogenesis (5) and promoting tumorigenesis (6). Moreover, EBV-related viral proteins and nucleic acids also induce epithelial-mesenchymal transition (EMT) (7) and promote tumor metastasis (8). However, the mechanism by which EBV causes tumorigenesis is not completely understood. Notably, the morbidity of EBV-associated tumors, such as NPC, does not match the prevalence of EBV (9). In addition, EBV-associated tumors have different prognoses; some patients live with the disease for several years, while others progress quickly (9). Classical parameters for disease diagnosis and monitoring, such as serum EBV antibody titers or EBV-DNA loads, display certain clinical limitations (10). To date, no superior EBV-specific biomarkers compared with the classical parameters have been identified. Therefore, it is important to study the biomechanisms of EBV-associated tumors and to identify specific biomarkers for these tumors. In recent decades, exosomes have become the focus of cancer research due to their intercellular communication ability. Exosomes are 40-100 nm-diameter vesicles that are released by cells (11). Almost all normal cells can secrete exosomes, and tumor cells appear to release more exosomes than normal cells (12). Recent studies have revealed that EBV-infected tumor cells can persistently release exosomes loaded with viral proteins or nucleic acids (13,14). As an important component of the tumor microenvironment (TME), exosomes are vectors by which tumor cells, including EBV-associated tumor cells, can transfer oncogenic cargo that can act on target cells (15). To date, a few studies have addressed exosomes derived from EBV+ tumors, and these studies suggest that the oncogenic molecules encoded by EBV not only display tumorigenic effects on uninfected cells via transfer through exosomes, but also exert potential immunosuppressive effects (14,16,17). Moreover, these exosomes can enter circulating body fluids and be transported throughout the body (10). Exosome separation technology is gradually advancing, and exosomes have been used as new drug delivery carriers in molecular targeted tumor therapy (18). EBV+ exosomes are expected to become a new biomarker or therapeutic target for EBV-associated tumors. The present review summarizes the important roles of exosomes in EBV-associated tumors to provide insight into the biomechanisms of these diseases from a new perspective.


Loading, release and uptake of exosomes

The formation of exosomes is a complex process, and numerous studies have described it in detail. The term exosome describes 40-100 nm-diameter vesicles that contain complex RNA and proteins. Exosomes form via the following axis: endosome-multivesicular body (MVB)-intraluminal vesicle (ILV). When MVBs fuse with the cell membrane, exosomes are released from parental cells (11). The formation of ILVs is the main process by which cargo, including proteins, lipids and nucleic acids, is loaded into vesicles. The endosomal sorting complex required for transport (ESCRT) machinery serves a critical role in the sorting of proteins into exosomes in parental cells (19). The RNA cargo of exosomes is enriched in small RNAs, especially microRNAs (miRNAs/miRs) (20). There are some other essential mechanisms of miRNA cargo loading in addition to the ESCRT machinery. Neutral sphingomyelinase 2 is the rate-limiting enzyme in the synthesis of ceramides, which could influence the loading of miRNAs into exosomes (21). Heterogeneous nuclear ribonucleoproteins (hnRNPs) are a family of conserved nuclear proteins that bind to nascent RNA polymerase II transcripts to produce hnRNP granules. Several hnRNPs, especially hnRNP A2B1 and hnRNP Q, are implicated in miRNA packaging into exosomes (22). hnRNPA2B1 can recognize and bind to specific motifs in the 3′ untranslated regions (3′UTRs) of miRNAs and then transport miRNAs into exosomes (23).

The intracellular movement of MVBs involves the microtubule network, and localization of MVBs to the plasma membrane requires kinesin-dependent movement toward microtubule plus ends (24). The release of exosomes depends on the forward motion of MVBs to fuse with the plasma membrane (25). Rab GTPases, a subfamily of proteins in the Ras superfamily of GTPases (26), and soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptor proteins can interact to induce exosome release (27).

Previous studies indicate that there are three main mechanisms underlying exosome uptake by recipient cells: i) Direct interaction (28); ii) fusion with the plasma membrane (29); and iii) internalization (30). In immune cells, major histocompatibility complex (MHC)-T cell receptor interactions can also facilitate the uptake of mutual exosomes (28). Once exosomes enter recipient cells, they trigger a series of biological effects through multiple pathways, including Erk1/2, Jak/STAT, NF-κB and PI3K/Akt signaling pathways (31).

Role of EBV in the biogenesis of exosomes

The mechanisms of exosome formation are briefly summarized in Fig. 1. Notably, some molecules encoded by EBV can participate in the loading processes. In B cell-derived exosomes, the 3′ ends of miRNAs are uridylated, and miRNAs from the parental cells share adenylated 3′ ends, suggesting that 3′ end modification of miRNAs may be another mechanism for sorting miRNAs into exosomes (32). Nkosi et al (33) revealed that the viral protein latent membrane protein 1 (LMP1) can interact with the ESCRT pathway and associated proteins, including CD63, Syntenin-1, programmed cell death 6 interacting protein, tumor susceptibility 101, human growth factor-regulated tyrosine kinase substrate (Hrs) and charged multivesicular body proteins (CHMPs). Moreover, the study demonstrated that the LMP1-interacting proteins Hrs and Syntenin-1 serve major roles in directing LMP1 into EVs for packaging and secretion (33).

Figure 1.

Overview of formation of exosomes and exosomes in the TME. EBV-encoded molecules, such as EBER and LMP-1, are loaded into exosomes and regulate the formation of exosomes. The endosomal sorting complex required for transport pathway and associated proteins, including CD63, Syntenin-1, Alix, TSG101 and Hrs, interact with LMP-1, inducing LMP-1 loading in exosomes. Tumor-derived exosomes target surrounding cells or enter the fluid circulation. Stress from the TME, such as hypoxia and acidic microenvironment, stimulates the synthesis and secretion of exosomes. TME, tumor microenvironment; EBV, Epstein-Barr virus; EBER, EBV-encoded RNA; LMP, latent membrane protein; Alix, programmed cell death 6 interacting protein; TSG101, tumor susceptibility 101; Hrs, human growth factor-regulated tyrosine kinase substrate; UCH-L1, ubiquitin C-terminal hydrolase L1; TRAF2, TNF receptor associated factor 2; CHMPs, charged multivesicular body proteins; MVE, multivesicular endosome; La, Lupus antigen; MHC, major histocompatibility complex; TCR, T cell receptor.

Exosomes in the TME

The TME is a complex interactome between tumor cells, adjacent cells (including adipocytes, fibroblasts, lymphocytes and dendritic cells) and the intercellular matrix. Cancer progression and metastasis are closely related to alterations in the TME; in particular, the characteristics of tumors, such as sustained proliferation, avoidance of immune surveillance, and activation of invasion and metastatic cascades, are influenced by the TME (34). In turn, cancer cells synthesize and secrete biomolecules to reprogram the surrounding cells and remodel the TME to be suitable for survival (35). The TME modulates numerous types of cell-cell communication through diverse signaling networks, including juxtacrine and paracrine interactions. Regarding paracrine signaling interactions, exosomes are an important and emerging mechanism of cell-cell communication (36). The TME also regulates the secretion of exosomes (37), and interactions of exosomes with the TME benefit the growth of the tumor. For example, exosomes derived from leukemia cells have been shown to accelerate cancer-associated fibroblast activation to remodel the TME to a more cancer-permissive state (38). Stress conditions, such as extracellular acidity and hypoxia, are common in the TME. On the one hand, the accumulation of lactic acid or H+ ions is a common characteristic of the TME, but TME acidity increases the release of tumor-derived exosomes (TEXs) (39). On the other hand, under hypoxic stress, tumor cells remodel the TME and facilitate angiogenesis by inducing the secretion of exosome-containing proteins associated with vascular endothelial growth factor (VEGF) signaling (40). Hypoxia can enhance miR-23a loading into lung cancer-derived exosomes. Endothelial cells take up exosomal miR-23a, which targets prolyl hydroxylase 1/2, resulting in the induction of hypoxia-inducible factor-1α (HIF1α) accumulation. Through this pathway, lung cancer cells remodel the TME and enhance tumor angiogenesis (41). Moreover, hypoxia-mediated enhancement of TEX release has also been observed in breast (42), bladder (43), prostate (44) and ovarian cancer (45) through multiple pathways, such as TGF-β2, TNF1α, IL-6, tumor susceptibility 101, Akt, integrin linked kinase 1 and β-catenin pathways.

EBV expresses multiple oncogenic molecules

EBV infection is gradually being recognized as endemic worldwide. It has taken several years to gain a clear understanding of the relationship between EBV and different types of human cancer, including Burkitt lymphoma, EBV+ diffuse large B cell lymphomas (DLBCLs), Hodgkin lymphoma (HL), NPC, EBVaGC, post-transplant lymphoproliferative disease (PTLD), natural killer (NK)/T cell lymphoproliferative disease (NK/T-LPD) and lymphoma (24).

EBV has a relatively large double-stranded DNA genome and expresses ~80 proteins and 46 functional small untranslated RNAs (46). EBV was the first human virus known to encode miRNAs (47), and EBV-miRNAs have recently become a research hotspot. As small non-coding RNAs that are 19-25 nucleotides in length and display partial homology to sequences in their target mRNAs, miRNAs can modulate gene expression in numerous species. Loading of an miRNA onto the 3′UTR of its target mRNA by the RNA-induced silencing complex results in either translational repression or degradation of the mRNA, ultimately leading to reduced protein synthesis (48). EBV expresses 25 different pre-miRNAs and at least 44 mature miRNAs. As one of the eight known human herpesviruses, EBV has two life cycle phases. Primary EBV infection occurs primarily in the epithelial cells of the host pharynx and is followed by infection of B lymphocytes (49). Primary infection usually occurs in the first years of life and does not produce symptoms. Subsequently, the virus is transmitted in saliva, and if primary infection is delayed until later in life, infectious mononucleosis may occur (50). As B lymphocytes carrying EBV enter the blood circulation, systemic EBV infection can occur (51,52). The virus then enters the second life cycle phase, known as latency. According to the latent genes expressed by EBV in host cells, latent infection in hosts can be classified into four types: 0, I, II and III) (53,54). The latency patterns of EBV gene expression in different infections are summarized in Table I.

Table I.

Patterns of latent gene expression in EBV-infected cells.

Table I.

Patterns of latent gene expression in EBV-infected cells.

A, Type 0

Gene Function Host cell (Refs.)
EBER Promote cell proliferation, inhibit apoptosis and transform cells. Infected dormant memory B cells (122)

B, Type I

Gene Function Host cell (Refs.)

EBNA1 Ensure the persistence of the viral genome in cells as they multiply. BL cells (5,7,8,99,123126)
EBV-miR-BART (BamHI-A rightward transcripts) Tumorigenesis: Promote angiogenesis, suppress apoptosis and promote host cell survival.
Tumor metastasis: EMT.
EBER Promote cell proliferation, inhibit apoptosis and transform cells.

C, Type II Function Host cell (Refs.)

EBNA1 Ensure the persistence of the viral genome in cells as they multiply. HL, NPC, DLBCL, EBVaGC and chronic lymphocytic leukemia cells (127131)
EBER Promote cell proliferation, inhibit apoptosis and transform cells.
EBV-miRs-BART Tumorigenesis: Promote angiogenesis, suppress apoptosis and promote host cell survival.
Tumor metastasis: EMT.
  LMP1 Act as a strongly oncogenic protein that can interact with numerous signaling molecules.

C, Type II Function Host cell (Refs.)

EBNA Immunoblastic lymphoma cells, DLBCL cells and EBV-LCLs (128,132134)
  EBNA1 Ensure the persistence of the viral genome in cells as they multiply.
  EBNA2 Act as a transcription factor that leads to the expression of viral LMP genes and ~300 host cell genes.
  LMP1 Act as a strongly oncogenic protein that can interact with numerous signaling molecules.

D, Type III Function Host cell (Refs.)

  EBV-miR-BHRF-1 (BamHI fragment H rightward open reading frame-1 miRNA)

[i] EBER, EBV-encoded RNA; EBNA, Epstein-Barr nuclear antigen 1; EBV, Epstein-Barr virus; miR, microRNA; BART, BamHI-A rightward transcripts; EMT, epithelial-mesenchymal transition; LMP, latent membrane protein; LP, leader protein; BHRF-1, BamHI fragment H rightward open reading frame-1; BL, Burkitt lymphoma; HL, Hodgkin lymphoma; NPC, nasopharyngeal carcinoma; DLBCL, diffuse large B cell lymphoma; EBVaGC, EBV-associated gastric cancer; LCL, lymphoblastoid cell line.

The EBV genome has been confirmed to encode viral proteins and nucleic acids associated with a variety of tumors. Moreover, the EBV-DNA load could be a prognostic factor in NPC (55,56), HL (57) and PTLD-DLBCL (58). However, some studies have indicated that in hydroa vacciniforme-like lymphoproliferative disorder (an EBV-associated NK/T cell lymphoproliferative disorder), the EBV-DNA load is not significantly correlated with patient prognosis (59,60). Therefore, the use of EBV-DNA load as a prognostic biomarker varies across tumors (61). The mechanisms by which the latent virus reactivates and influences NK/T cells, B cells and other cells requires further investigation. In addition, as aforementioned, the high prevalence of EBV does not match the incidence of EBV-associated tumors. Thus, EBV infection may not be the key mechanism underlying EBV-associated tumorigenesis. The proteins or nucleic acids encoded by EBV may serve pivotal roles in tumorigenesis and tumor development as tumor regulators. In addition, exosomes serve essential roles in the transfer of oncogenic molecules, as well as in the tumorigenesis and tumor metastasis of EBV-associated tumors (62,63).

Different EBV+ tumor cells secrete exosomes acting on various target cells

The type of latent infection varies among individuals, although type 0 is the most widespread, resulting in the expression of various genes corresponding to latency types. Interestingly, the amount of exosomes secreted by EBV+ cells differs among the latency patterns, and cells with type III latency secrete the most exosomes (13). In addition, EBV-associated tumors exhibit different latency patterns and TMEs. Therefore, exosomes from different tumor sources have different functions due to their different parental cells and target cells (46). The functions of exosomes derived from cells of different EBV+ tumors are summarized in this chapter.

Functions of exosomes derived from EBV+ B cells

Once EBV infection occurs, the viral genome is disassembled and integrated into the host genome. Thus, even in latency, EBV+ B cells could persistently express viral proteins and nucleic acids (64). LMP1 is a major oncoprotein of EBV, and numerous studies have demonstrated that it can be loaded on the membrane of exosomes (14,33,65,66). LMP1 also exists in exosomes derived from LMP1-transfected DG75 cells (a Burkitt lymphoma cell line). DG75 exosomes can be taken up by isolated B cells within the peripheral blood mononuclear cell population, which leads to enhanced proliferation and induces B cell differentiation toward a plasmablast-like phenotype via induction of activation-induced cytidine deaminase and the production of circle and germline transcripts for IgG1 in B cells (62). In vitro, after infection of B cells, LMP1 induces immortalization and aberrant proliferation, leading to the development of lymphoblastoid cell lines (LCLs) (67). The N-terminus and transmembrane domain 1 are sufficient for targeting LMP1 to extracellular vesicles (EVs) (68). Kobayashi et al (14) reported that ubiquitin C-terminal hydrolase-L1 and C-terminal farnesylation, a post-translational lipid modification, contribute to the direction of LMP1 to exosomes. Moreover, Rialland et al (69) found that the B cell receptor can modulate the protein content of exosomes upon stimulation and target its bound antigen to these vesicles. On the other hand, exosomes derived from LCLs carry an EBV glycoprotein, gp350, and preferentially target B cells via the interaction of this glycoprotein with its ligand, CD21 (70). In addition, these exosomes contain high levels of MHC-II molecules, which induce homogeneous antigen-specific T cell responses (66). The transmembrane freedom of exosomes is important for cellular interactions and this property might become the basis of exosome-targeted therapy.

Exosomes released from EBV+ B cells are internalized by recipient cells primarily via caveolin-dependent endocytosis (71). When exosomes derived from EBV+ B cells enter the TME, they can create an immunosuppressive microenvironment that affects T cell immune responses to ensure the proliferation of tumor cells. Cells with latent EBV infection can continuously produce EBV-encoded RNAs (EBERs), which elicit proinflammatory responses after sensing by pathogen recognition receptors (72,73). Lupus antigen (La) is an abundant RNA binding protein in the nucleus of latently infected B cells that binds nascent viral Pol III transcripts, protecting the 3′ ends from degradation by exonucleases (74). EBERs are transported from the nucleus to the cytoplasm and shed in exosomes by binding to La (16). Based on these studies, Baglio et al (75) proposed that by interacting with La and loading into exosomes, EBV nuclear 5′pppEBER1 escapes cytosolic detection in cells with established latent infection. Then, the viral cargo loads are internalized by plasmacytoid dendritic cells (pDCs), triggering antiviral immunity through exosomes. Another study showed that exosomes secreted from P3HR1 cells (an EBV+ Burkitt lymphoma B cell line) can increase the production of indoleamine 2,3-dioxygenase (IDO), TNF-α and interleukin (IL)-6 in human monocyte-derived macrophages (MDMs) via the retinoic acid-inducible gene I pathway. Moreover, EBER-1-activated IDO in MDMs suppresses the proliferation of T lymphocytes and diminishes the cytolytic activity of CD8+ T cells (76). Thus, EBER1+ exosomes derived from EBV+ B cells might promote tumorigenesis by inhibiting cellular immunity in the TME.

EBV-miRNAs are loaded into exosomes to induce a series of downstream effects (77). Higuchi et al (78) showed that exosomes derived from EBV+ lymphoma cells can regulate the activity of macrophages and induce the immunoregulatory phenotype in vitro. In this process, the expression levels of TNF-α, IL-10 and ARG1 are partially regulated by EBV-BamHI A rightward transcripts (BART)-miRNAs. Ito et al (63) observed that a phosphatidylserine-exposing subset of EVs secreted from lymphoma cells transformed with the EBV strain Akata converted surrounding phagocytes into tumor-associated macrophages (TAMs) by inducing an inflammatory response partially mediated by EBV-miRNAs. Using mass spectrometric analysis, the study indicated that several immunomodulatory proteins, especially integrin αLβ2 and fibroblast growth factor 2 (FGF2), are key factors in the TAM-inducing ability of EVs. Moreover, in the clinic, higher loads of BART miRNAs correlate with worse outcomes in elderly patients with EBV+ DLBCL. Furthermore, EBV-BART-miRNAs might be the link between EBV+ B cells and uninfected T cells or NK cells. Haneklaus et al (79) showed that exosomal EBV-miR-BART15 released from EBV+ B cells can enter uninfected T cells, targeting the miR-223 binding site in the NLR family pyrin domain containing 3 3′UTR to inhibit inflammasome-mediated IL-1β production, which was consistent with previous interpretations (80,81). T cells can be suppressed by LMP1+ exosomes (66); thus, EBV+ exosomes display immunosuppressive effects. Extranodal NK/T cell lymphoma, nasal type (ENKTCL) is a rare EBV-associated non-Hodgkin lymphoma (82). However, the mechanism of EBV entry into NK cells remains unknown. Lee et al (83) reported that EBV mRNAs and CD21 RNA can be transferred into NK cells from B cells by exosomes. However, this transfer is not sufficient to maintain EBV persistence or allow EBV entry into NK cells. Therefore, whether EBV genomic components can affect NK/T cells via exosomes requires further investigation.

These studies indicate that exosomes derived from EBV+ B cells can affect uninfected cells, and highlight the immunomodulatory function and oncogenic effect of exosomes. EBV hijacks host cells to build an immunosuppressive TME by secreting exosomes. Moreover, Ahmed et al (84) reported that exosomes derived from cells with both type I and III latent EBV infection induce apoptosis in B cells, T cells and epithelial cells via the Fas cell surface death receptor (Fas)/Fas ligand (FasL) pathway. As the majority of studies of exosomes derived from EBV+ B cells have been conducted in vitro, further studies, especially in vivo studies, are needed to clarify the complete roles of exosomes.

Functions of exosomes derived from nasopharyngeal epithelial cells

NPC is a malignant tumor derived from nasopharyngeal epithelial cells that has a high incidence in southern China, Mediterranean Africa and some regions of the Middle East (85). The role of EBV in NPC has been studied for decades. Virtually all NPCs are EBV+ (64); however, the complete mechanisms of EBV in the development and progression of NPC remain unclear. Viral proteins or nucleic acids might be involved in these processes. In recent years, researchers have focused on the roles of exosomes, and these studies are summarized to highlight the role of EBV in NPC.

Although the oncogenicity of LMP1 is known, there are no effective strategies to target this oncoprotein. With further studies, researchers have begun to focus on EBV+ exosomes. In 2006, Keryer-Bibens et al (86) first demonstrated that NPC cells can release HLA class II+ exosomes containing galectin 9 and/or LMP1. Galectin-9 is a ligand of the membrane receptor T cell immunoglobulin and mucin domain-containing protein 3, which is able to induce apoptosis in mature Th1 lymphocytes, weakening immunological surveillance (87). A previous study demonstrated that LMP1 can target the epidermal growth factor receptor (EGFR), inducing cell proliferation (88). Moreover, LMP1 increases the loading of EGFR into exosomes secreted by NPC cells, and exosomes containing LMP1 and EGFR are taken up by epithelial cells, endothelial cells and fibroblasts, which activates the ERK and PI3K/Akt pathways to affect cell proliferation (89). On the other hand, HIF1α regulates numerous key aspects of tumor development and progression by promoting increases in proliferation, invasiveness and neoangiogenesis (90). Aga et al (91) demonstrated that LMP1+ exosomes secreted by NPC cell lines contain HIF1α. Furthermore, LMP1+ exosomes and HIF1α can counterbalance the levels of E-cadherin and N-cadherin in recipient cells, consistent with EMT-associated changes. FGF-2, a member of the FGF family, is active in embryogenesis and morphogenesis, and serves a key role as an angiogenic factor involved in tumor progression and invasion (92). Ceccarelli et al (93) demonstrated that FGF-2 is packaged into exosomes and LMP1 selectively promotes this secretory process. LMP1 can interact with nucleic acids in addition to human proteins. For instance, miR-203 functions as a tumor suppressor in NPC and can be downregulated by LMP1 (94). A further study demonstrated that aspirin can reverse EMT and exosomal LMP1 might serve a pivotal role in this process. Exosomal LMP1 exhibited potential EMT-inducing ability, aspirin suppressed exosomal LMP1 secretion from EBV+ cells by influencing NF-κB, and a decrease in exosomal LMP1 uptake alleviated the inhibition of miR-203 by LMP1. The aforementioned results were further confirmed in an in vivo study; thus, aspirin could inhibit NPC lung metastasis by reversing the LMP1/NF-kB/exosomal LMP1/miR-203 axis in nude mice (17).

Weakening or evading the immune surveillance function of lymphocytes is beneficial to the proliferation of tumor cells. Mrizak et al (95) showed that NPC cell-derived exosomes (NPC-Exos) express CCL20 on their surface, which prioritizes the infiltration of regulatory T cells (Tregs) into the tumor. In addition, NPC-Exos recruit CD4+ T cells and induce their conversion into suppressive Tregs. Under induction by NPC-Exos, Tregs change their phenotype and their immunosuppressive ability is enhanced. These findings show that EBV+ exosomes can exert immunosuppressive effects not only by affecting pDCs, MDMs and CD8+ T cells, but also by recruiting Tregs.

EBV-BART-miRNAs have been found in exosomes secreted from infected epithelial cells, and these miRNAs can affect mitochondrial respiration in exosome recipient cells to modify the TME to support the growth of infected cells, thereby contributing to viral fitness (96). In another report, Meckes et al (89) showed that EBV-BART-miRNAs (including miR-BART-1, 4, 5, 7, 9, 11, 12, 13, and 16) are also selectively loaded into exosomes secreted from cultured EBV+ NPC cells. These viral miRNAs have been found to have biological functions and to be involved in molecular mechanisms associated with tumor immune evasion, proliferation, apoptosis resistance, invasion and metastasis (97). EBV-miR-BART3 can target the tumor suppressor integrator complex subunit 6 to promote cell proliferation and transformation in NPC (98). In a nude mouse model, EBV-BART3-3p was found to directly target the tumor suppressor gene tumor protein 53, which led to inhibition of senescence in GC cells, suppression of NK cells and macrophage infiltration into tumors (99), which are post-transcriptional regulation processes independent of genetic mutations. However, few studies have addressed whether EBV-miRNAs can mediate these changes through exosomes, and the specific mechanism remains unclear. Tumor occurrence results from the accumulation of a number of different factors. As the functions of EBV+ exosomes in NPC have been gradually explored, it can be speculated that viral oncogenic cargo might be transferred to uninfected cells through exosomes, resulting in the occurrence or progression of NPC.

Similarly, exosomes derived from NPC cells share analogous immunosuppressive functions like those of exosomes from EBV+ B cells. Importantly, exosomes from NPC cells could also induce the angiogenesis, EMT and metastasis of tumors (17,95). Therefore, we speculate that targeting EBV+ exosomes is of significance for the treatment of NPC, and might be able to reverse the progression of tumors by blocking tumor cell immune escape and inhibiting tumor angiogenesis and EMT at the same time.

Exosomes derived from EBV-associated gastric cancer cells

EBVaGC accounts for ~10% of GC cases worldwide, with variable frequencies among geographic regions (100). In 1990, a possible association with EBV was first reported in a case of gastric carcinoma (101). To date, studies investigating EBV+ exosomes in EBVaGC are limited. In 2013, Choi et al (102) reported that miR-BART15-3p is enriched in exosomes derived from EBVaGC cells and can induce apoptosis partially by inhibiting the translation of the apoptosis inhibitor baculovirus inhibitor of apoptosis repeat-containing ubiquitin-conjugating enzyme. However, DCs are pivotal to tumor immunity (103), and Hinata et al (104) found that the maturation of DCs is suppressed by exosomes derived from EBV+ epithelial cells, which weakens tumor immunity. The aforementioned studies show the paradoxical functions of EBV+ exosomes, including inhibition of host immunity while promoting EBV+ cell apoptosis, which might explain why the prognosis of EBVaGC is favorable compared with that of other types of GC (105).

Although there are a number of different kinds of EBV-associated tumors, they primarily include B cell lymphoma, NPC and EBVaGC. These three different tumors have different TMEs but share an analogous immunosuppressive characteristic, which might be induced by EBV+ exosomes (63,95,104). The known mechanisms of different EBV+ tumor cell exosomes acting on various target cells are summarized in Fig. 2.

Figure 2.

Role of EBV+ exosomes in the TME of B cell lymphoma, NPC and EBVaGC. For B cell lymphoma, EBV+ exosomes primarily act on lymphocytes with immunomodulatory functions. The EBV+ exosomes induce the proliferation and differentiation of naive B cells into plasmablast-like B cells. EBV+ exosomes also target macrophages, leading to transformation into TAMs and stimulating the secretion of immunosuppressive cytokines to inhibit CD8+ T cells. Moreover, EBV+ exosomes inhibit T cell synthesis of IL-1β. In the TME of NPC, EBV+ exosomes exert a strong immunosuppressive function, which is induced by recruiting Tregs and promoting CD8+ T cell apoptosis. In addition, EBV+ exosomes from NPC target endothelium, fibroblasts and epithelium to stimulate cell growth by delivering EGFR. EBV+ exosomes from NPC also stimulate EMT, promoting tumor metastasis and angiogenesis. The immunosuppressive effects of EBV+ exosomes from EBVaGC are primarily achieved via inhibiting pDCs. miR-BART15-3p is enriched in exosomes from EBVaGC cells and can induce the apoptosis of target cells, including tumor cells. EBV, Epstein-Barr virus; TME, tumor microenvironment; NPC, nasopharyngeal carcinoma; EBVaGC, EBV-associated gastric cancer; TAM, tumor-associated macrophages; EGFR, epidermal growth factor receptor; EMT, epithelial-mesenchymal transition; pDC, plasmacytoid dendritic cells; miR, microRNA; BART, BamHI-A rightward transcripts; NLRP, NLR family pyrin domain; ARG1, arginase 1; IL, interleukin; EBER, EBV-encoded RNA; TCR, T cell receptor; MHC, major histocompatibility complex; LMP, latent membrane protein; FGF, fibroblast growth factor; EGFR, epidermal growth factor receptor; HIF, hypoxia-inducible factor; CCL, C-C motif chemokine ligand; EBNA, Epstein-Barr nuclear antigen; La, lupus antigen; BHFR, BamHI fragment H rightward open reading frame; BRUCE, baculovirus inhibitor of apoptosis repeat-containing ubiquitin-conjugating enzyme; DC, dendritic cell.

Circulating EBV+ exosomes act as a biomarker for EBV-associated tumor diagnosis

As viral oncoproteins and nucleic acids are contained in exosomes, these EBV+ exosome-derived targets could be helpful diagnostic markers. Moreover, exosomes are present and can be detected in almost all biological fluids, including serum, plasma, semen, breast milk, cerebrospinal fluid, urine, saliva, ascites, amniotic fluid and bronchoalveolar lavage fluid (10), which may overcome the limitations of the specificity of classical EBV infection detection methods. For example, EBER in situ hybridization is performed primarily with biopsy tissues, whereas enzyme immunoassays used to determine EBV antibody titers and polymerase chain reaction used to determine EBV-DNA loads are usually performed with plasma (10). Moreover, as the gold standard, the sensitivity of EBER ISH varies across tissues.

In 2005, Caby et al (106) first identified exosomes in blood, indicating that exosomes could travel throughout the body and modulate targeted cells via the circulatory system. Subsequently, Houali et al (107) detected LMP1 and EBV BamHI-A Rightward Frame 1 in serum and saliva from North African and Chinese patients with NPC. Other studies have further suggested that EBV+ exosomes could be used as biomarkers not only for the diagnosis of EBV infection, but also for predicting the prognosis of patients with EBV-associated tumors. A previous study on ENKTCL showed elevated expression levels of LMP1 and LMP2A in tumor cells. High LMP1 expression was associated with positive B symptoms, and the expression of both LMP1 and LMP2A showed a significant correlation with overall patient survival (108). Due to the noninvasiveness of obtaining exosomes from body fluids, LMP1+ and LMP2A+ exosomes might be promising biomarkers of ENKTCL in the clinic. Cyclophilin A (CYPA) is a member of the immunophilin family (109). Liu et al (110) demonstrated that both the serum and exosomal CYPA levels of patients with NPC were significantly higher compared with those of normal cases. Moreover, the level of CYPA was positively correlated with LMP1 in NPC exosomes. Therefore, the authors hypothesized that CYPA combined with EBV-viral capsid antigen-IgA may be a more discriminatory biomarker panel in the diagnosis of NPC. However, whether LMP1+ and LMP2A+ exosomes have prognostic value requires further investigation.

In addition to viral proteins, EBV-miRs have been shown to be potential diagnostic biomarkers for EBV-associated cancer. Zhang et al (111) demonstrated that EBV-miR-BART7 and EBV-miR-BART13 can serve as important biomarkers for NPC diagnosis and the prediction of treatment efficacy. Similarly, Wardana et al (112) found that overexpression of circulating EBV miR-BART7 correlated with positive regional lymph node status, highlighting the diagnostic and prognostic values of circulating miR-BART7 for patients with NPC. A number of the 49 EBV-encoded miRNAs have been proven to serve key roles in the development of NPC (113). miRNAs encapsulated in exosomes are protected from degradation by RNases. Thus, exosome encapsulation is more conducive to the detection of viral miRNAs and can reduce the number of false negatives caused by degradation during specimen transportation (114). In the early years, the separation technology of exosomes was immature and the extraction cost was high, which hindered the study of exosomes (115). With the development of separation technologies for isolating exosomes from body fluids, the detection of exosomes as biomarkers for diseases may become a mainstream approach.

Future perspectives: Exosomes could be utilized as a new therapeutic method

As aforementioned, exosomes synthesized by different parental cells load different molecules and target different cells. Specifically, exosomes are ideal tools for miRNA-based interactions between tumor cells. In turn, tumor cells persistently secrete exosomes and act on peritumoral cells, remodeling the TME to facilitate the growth of tumor cells. Therefore, modification of exosomes, especially the loaded miRNAs, may serve as a novel therapeutic strategy for cancer. For example, loss or downregulation of miR-122 is closely related to poor prognosis and metastasis in hepatocellular carcinoma (HCC) (116). Based on this finding, Lou et al (117) constructed an miR-122 expression plasmid, which was transfected into adipose tissue-derived mesenchymal stem cells (AMSCs). Then, AMSC-derived exosomes were harvested and added to recipient HCC cells. Interestingly, miR-122-transfected AMSCs effectively packaged miR-122 into secreted exosomes and provided HCC cells with sensitivity to chemotherapeutic agents through altering miR-122-target gene expression. Moreover, Wang et al (118) overexpressed EBV-miR-BART10-5p and hsa-miR-18a, which strongly induced angiogenesis in vitro and in vivo. Mechanistically, the association of viral miRNAs with human miRNAs was found to promote cancer angiogenesis and to involve the concordant downregulation of sprouty RTK signaling antagonist 3 (Spry3; a tumor suppressor) expression, activating Spry3/MEK/Erk-dependent pathways and regulating the expression of VEGF and HIF1a in a Spry3-dependent manner. Moreover, iRGD-tagged exosomes containing antagomiR-BART10-5p and antagomiR-18a were utilized to suppress the angiogenesis and growth of NPC.

An immunosuppressive TME exists in most EBV-associated tumors, which impedes the efficacy of immunotherapies (119). The majority of previous studies have confirmed that exosomes derived from EBV+ tumor cells serve a role in inhibiting body immunity and promoting tumor cell immune evasion in the process of tumor progression (63,95,104). Therefore, targeting EBV+ exosomes is considered as a promising new treatment for EBV+ tumors. Wang et al (120) found that exosomes derived from phosphoantigen-expanded Vδ2-T (Vδ2-T-Exos) cells could promotes EBV antigen-specific CD4 and CD8 T cell expansion and kill EBV-associated tumor cells through FasL/TNF-related apoptosis-inducing ligand pathways. These findings suggested a strategy for the treatment of EBV-associated tumors using Vδ2-T-Exos.

The application of targeting EBV+ exosomes for antitumor therapy requires further investigation. However, the aforementioned findings warrant future studies to investigate the potential of exosomes as anti-EBV-associated tumor-specific therapeutic targets. For example, preventing EBV-encoded molecules from loading into exosomes or inhibiting the release of EBV+ exosomes might be serve as novel strategies. Given the recent increased interest in the use of exosomes as vectors for targeted therapy with nanomaterials (121), this therapeutic approach may offer clinical potential.


EBV has been studied for decades. EBV is closely related to numerous kinds of tumors in terms of both epidemiology and molecular biology. However, the key pathogenic mechanisms of the virus may not be the viral particles themselves but instead the molecules encoded by the virus, indicating that antiviral drugs may not be useful. Exosomes act as perfect carriers for these viral molecules to protect them from degradation by host enzymes and transport them to other cells with the continuous influence of target cells. In different TMEs, EBV+ tumor exosomes target different cells but share similar immunosuppressive functions. We speculated that the viral molecules loaded in the exosomes served a pivotal role. To date, therapies for EBV+ tumors have displayed limited effectiveness, and a vaccine for EBV has not yet been produced. In the future, the treatment and prevention of EBV+ tumors may focus on EBV+ exosomes, and exosome-based disease monitoring and treatment, as well as viral vaccines may have potential, but these approaches require further exploration.


Not applicable.


The present study was supported by the Department of Science and Technology of Sichuan Province (grant no. 2019YFS0250 and 2018SZ0162).

Availability of data and materials

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Authors' contributions

WC drafted, proofread and revised the manuscript. YX edited and revised the manuscript. TW edited the manuscript. TW and LW provided the project financial support. LW supervised and oversaw the production of this review. All authors have read and approved the final manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.



Epstein MA, Achong BG and Barr YM: Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Lancet. 1:702–703. 1964. View Article : Google Scholar : PubMed/NCBI


Vockerodt M, Yap LF, Shannon-Lowe C, Curley H, Wei W, Vrzalikova K and Murray PG: The Epstein-Barr virus and the pathogenesis of lymphoma. J Pathol. 235:312–322. 2015. View Article : Google Scholar : PubMed/NCBI


Tsao SW, Tsang CM, To KF and Lo KW: The role of Epstein-Barr virus in epithelial malignancies. J Pathol. 235:323–333. 2015. View Article : Google Scholar : PubMed/NCBI


Niller HH, Banati F, Salamon D and Minarovits J: Epigenetic alterations in Epstein-Barr virus-associated diseases. Adv Exp Med Biol. 879:39–69. 2016. View Article : Google Scholar : PubMed/NCBI


Lyu X, Wang J, Guo X, Wu G, Jiao Y, Faleti OD, Liu P, Liu T, Long Y, Chong T, et al: EBV-miR-BART1-5P activates AMPK/mTOR/HIF1 pathway via a PTEN independent manner to promote glycolysis and angiogenesis in nasopharyngeal carcinoma. PLoS Pathog. 14:e10074842018. View Article : Google Scholar : PubMed/NCBI


Hulse M, Johnson SM, Boyle S, Caruso LB and Tempera I: Epstein-Barr virus-encoded latent membrane protein 1 and B-cell growth transformation induce lipogenesis through fatty acid synthase. J Virol. 95:e01857–20. 2021. View Article : Google Scholar : PubMed/NCBI


Huang J, Qin Y, Yang C, Wan C, Dai X, Sun Y, Meng J, Lu Y, Li Y, Zhang Z, et al: Downregulation of ABI2 expression by EBV-miR-BART13-3p induces epithelial-mesenchymal transition of nasopharyngeal carcinoma cells through upregulation of c-JUN/SLUG signaling. Aging (Albany NY). 12:340–358. 2020. View Article : Google Scholar : PubMed/NCBI


Cai L, Ye Y, Jiang Q, Chen Y, Lyu X, Li J, Wang S, Liu T, Cai H, Yao K, et al: Epstein-Barr virus-encoded microRNA BART1 induces tumour metastasis by regulating PTEN-dependent pathways in nasopharyngeal carcinoma. Nat Commun. 6:73532015. View Article : Google Scholar : PubMed/NCBI


Wong Y, Meehan MT, Burrows SR, Doolan DL and Miles JJ: Estimating the global burden of Epstein-Barr virus-related cancers. J Cancer Res Clin Oncol. Oct 27–2021.(Epub ahead of print). View Article : Google Scholar


AbuSalah MAH, Gan SH, Al-Hatamleh MAI, Irekeola AA, Shueb RH and Yean Yean C: Recent advances in diagnostic approaches for Epstein-Barr virus. Pathogens. 9:2262020. View Article : Google Scholar : PubMed/NCBI


Théry C, Zitvogel L and Amigorena S: Exosomes: Composition, biogenesis and function. Nat Rev Immunol. 2:569–579. 2002. View Article : Google Scholar : PubMed/NCBI


Raposo G and Stoorvogel W: Extracellular vesicles: Exosomes, microvesicles, and friends. J Cell Biol. 200:373–383. 2013. View Article : Google Scholar : PubMed/NCBI


Nanbo A, Katano H, Kataoka M, Hoshina S, Sekizuka T, Kuroda M and Ohba Y: Infection of Epstein-Barr virus in type III latency modulates biogenesis of exosomes and the expression profile of exosomal miRNAs in the burkitt lymphoma mutu cell lines. Cancers (Basel). 10:2372018. View Article : Google Scholar : PubMed/NCBI


Kobayashi E, Aga M, Kondo S, Whitehurst C, Yoshizaki T, Pagano JS and Shackelford J: C-terminal farnesylation of UCH-L1 plays a role in transport of Epstein-Barr virus primary oncoprotein LMP1 to exosomes. mSphere. 3:e00030–18. 2018. View Article : Google Scholar : PubMed/NCBI


Villarroya-Beltri C, Baixauli F, Gutiérrez-Vázquez C, Sánchez-Madrid F and Mittelbrunn M: Sorting it out: Regulation of exosome loading. Semin Cancer Biol. 28:3–13. 2014. View Article : Google Scholar : PubMed/NCBI


Ahmed W, Tariq S and Khan G: Tracking EBV-encoded RNAs (EBERs) from the nucleus to the excreted exosomes of B-lymphocytes. Sci Rep. 8:154382018. View Article : Google Scholar : PubMed/NCBI


Zuo L, Xie Y, Tang J, Xin S, Liu L, Zhang S, Yan Q, Zhu F and Lu J: Targeting exosomal EBV-LMP1 transfer and miR-203 expression via the NF-κB pathway: The therapeutic role of aspirin in NPC. Mol Ther Nucleic Acids. 17:175–184. 2019. View Article : Google Scholar : PubMed/NCBI


Chen H, Wang L, Zeng X, Schwarz H, Nanda HS, Peng X and Zhou Y: Exosomes, a new star for targeted delivery. Front Cell Dev Biol. 9:7510792021. View Article : Google Scholar : PubMed/NCBI


Henne WM, Buchkovich NJ and Emr SD: The ESCRT pathway. Dev Cell. 21:77–91. 2011. View Article : Google Scholar : PubMed/NCBI


Pegtel DM, Cosmopoulos K, Thorley-Lawson DA, van Eijndhoven MA, Hopmans ES, Lindenberg JL, de Gruijl TD, Würdinger T and Middeldorp JM: Functional delivery of viral miRNAs via exosomes. Proc Natl Acad Sci USA. 107:6328–6333. 2010. View Article : Google Scholar : PubMed/NCBI


Kosaka N, Iguchi H, Hagiwara K, Yoshioka Y, Takeshita F and Ochiya T: Neutral sphingomyelinase 2 (nSMase2)-dependent exosomal transfer of angiogenic microRNAs regulate cancer cell metastasis. J Biol Chem. 288:10849–10859. 2013. View Article : Google Scholar : PubMed/NCBI


Val S, Krueger A, Poley M, Cohen A, Brown K, Panigrahi A and Preciado D: Nontypeable Haemophilus influenzae lysates increase heterogeneous nuclear ribonucleoprotein secretion and exosome release in human middle-ear epithelial cells. FASEB J. 32:1855–1867. 2018. View Article : Google Scholar : PubMed/NCBI


Villarroya-Beltri C, Gutiérrez-Vázquez C, Sánchez-Cabo F, Pérez-Hernández D, Vázquez J, Martin-Cofreces N, Martinez-Herrera DJ, Pascual-Montano A, Mittelbrunn M and Sánchez-Madrid F: Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun. 4:29802013. View Article : Google Scholar : PubMed/NCBI


Martín-Cófreces NB, Baixauli F and Sánchez-Madrid F: Immune synapse: Conductor of orchestrated organelle movement. Trends Cell Biol. 24:61–72. 2014. View Article : Google Scholar : PubMed/NCBI


Morelli AE, Larregina AT, Shufesky WJ, Sullivan ML, Stolz DB, Papworth GD, Zahorchak AF, Logar AJ, Wang Z, Watkins SC, et al: Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells. Blood. 104:3257–3266. 2004. View Article : Google Scholar : PubMed/NCBI


Blanc L and Vidal M: New insights into the function of Rab GTPases in the context of exosomal secretion. Small GTPases. 9:95–106. 2018. View Article : Google Scholar : PubMed/NCBI


Jahn R and Scheller RH: SNAREs-engines for membrane fusion. Nat Rev Mol Cell Biol. 7:631–643. 2006. View Article : Google Scholar : PubMed/NCBI


Tkach M, Kowal J, Zucchetti AE, Enserink L, Jouve M, Lankar D, Saitakis M, Martin-Jaular L and Théry C: Qualitative differences in T-cell activation by dendritic cell-derived extracellular vesicle subtypes. EMBO J. 36:3012–3028. 2017. View Article : Google Scholar : PubMed/NCBI


Prada I and Meldolesi J: Binding and fusion of extracellular vesicles to the plasma membrane of their cell targets. Int J Mol Sci. 17:12962016. View Article : Google Scholar : PubMed/NCBI


Tian T, Zhu YL, Hu FH, Wang YY, Huang NP and Xiao ZD: Dynamics of exosome internalization and trafficking. J Cell Physiol. 228:1487–1495. 2013. View Article : Google Scholar : PubMed/NCBI


Yang L, Huang X, Guo H, Wang L, Yang W, Wu W, Jing D and Shao Z: Exosomes as efficient nanocarriers in osteosarcoma: Biological functions and potential clinical applications. Front Cell Dev Biol. 9:7373142021. View Article : Google Scholar : PubMed/NCBI


Koppers-Lalic D, Hackenberg M, Bijnsdorp IV, van Eijndhoven MAJ, Sadek P, Sie D, Zini N, Middeldorp JM, Ylstra B, de Menezes RX, et al: Nontemplated nucleotide additions distinguish the small RNA composition in cells from exosomes. Cell Rep. 8:1649–1658. 2014. View Article : Google Scholar : PubMed/NCBI


Nkosi D, Sun L, Duke LC, Patel N, Surapaneni SK, Singh M and Meckes DG Jr: Epstein-Barr virus LMP1 promotes syntenin-1- and Hrs-induced extracellular vesicle formation for its own secretion to increase cell proliferation and migration. mBio. 11:e00589–20. 2020. View Article : Google Scholar : PubMed/NCBI


Friedl P and Alexander S: Cancer invasion and the microenvironment: Plasticity and reciprocity. Cell. 147:992–1009. 2011. View Article : Google Scholar : PubMed/NCBI


Zhao TJ, Zhu N, Shi YN, Wang YX, Zhang CJ, Deng CF, Liao DF and Qin L: Targeting HDL in tumor microenvironment: New hope for cancer therapy. J Cell Physiol. 236:7853–7873. 2021. View Article : Google Scholar : PubMed/NCBI


Quail DF and Joyce JA: Microenvironmental regulation of tumor progression and metastasis. Nat Med. 19:1423–1437. 2013. View Article : Google Scholar : PubMed/NCBI


de Jong OG, Verhaar MC, Chen Y, Vader P, Gremmels H, Posthuma G, Schiffelers RM, Gucek M and van Balkom BW: Cellular stress conditions are reflected in the protein and RNA content of endothelial cell-derived exosomes. J Extracell Vesicles. 1:2012. View Article : Google Scholar : PubMed/NCBI


Zhao H, Yang L, Baddour J, Achreja A, Bernard V, Moss T, Marini JC, Tudawe T, Seviour EG, San Lucas FA, et al: Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. Elife. 5:e102502016. View Article : Google Scholar : PubMed/NCBI


Parolini I, Federici C, Raggi C, Lugini L, Palleschi S, De Milito A, Coscia C, Iessi E, Logozzi M, Molinari A, et al: Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem. 284:34211–34222. 2009. View Article : Google Scholar : PubMed/NCBI


Park JE, Tan HS, Datta A, Lai RC, Zhang H, Meng W, Lim SK and Sze SK: Hypoxic tumor cell modulates its microenvironment to enhance angiogenic and metastatic potential by secretion of proteins and exosomes. Mol Cell Proteomics. 9:1085–1099. 2010. View Article : Google Scholar : PubMed/NCBI


Hsu YL, Hung JY, Chang WA, Lin YS, Pan YC, Tsai PH, Wu CY and Kuo PL: Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1. Oncogene. 36:4929–4942. 2017. View Article : Google Scholar : PubMed/NCBI


King HW, Michael MZ and Gleadle JM: Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer. 12:4212012. View Article : Google Scholar : PubMed/NCBI


Xue M, Chen W, Xiang A, Wang R, Chen H, Pan J, Pang H, An H, Wang X, Hou H and Li X: Hypoxic exosomes facilitate bladder tumor growth and development through transferring long non-coding RNA-UCA1. Mol Cancer. 16:1432017. View Article : Google Scholar : PubMed/NCBI


Ramteke A, Ting H, Agarwal C, Mateen S, Somasagara R, Hussain A, Graner M, Frederick B, Agarwal R and Deep G: Exosomes secreted under hypoxia enhance invasiveness and stemness of prostate cancer cells by targeting adherens junction molecules. Mol Carcinog. 54:554–565. 2015. View Article : Google Scholar : PubMed/NCBI


Dorayappan KDP, Wanner R, Wallbillich JJ, Saini U, Zingarelli R, Suarez AA, Cohn DE and Selvendiran K: Hypoxia-induced exosomes contribute to a more aggressive and chemoresistant ovarian cancer phenotype: A novel mechanism linking STAT3/Rab proteins. Oncogene. 37:3806–3821. 2018. View Article : Google Scholar : PubMed/NCBI


Farrell PJ: Epstein-Barr virus and cancer. Annu Rev Pathol. 14:29–53. 2019. View Article : Google Scholar : PubMed/NCBI


Pfeffer S, Zavolan M, Grässer FA, Chien M, Russo JJ, Ju J, John B, Enright AJ, Marks D, Sander C and Tuschl T: Identification of virus-encoded microRNAs. Science. 304:734–736. 2004. View Article : Google Scholar : PubMed/NCBI


Meister G: miRNAs get an early start on translational silencing. Cell. 131:25–28. 2007. View Article : Google Scholar : PubMed/NCBI


Hadinoto V, Shapiro M, Sun CC and Thorley-Lawson DA: The dynamics of EBV shedding implicate a central role for epithelial cells in amplifying viral output. PLoS Pathog. 5:e10004962009. View Article : Google Scholar : PubMed/NCBI


Münz C: Epstein-Barr Virus-specific immune control by innate lymphocytes. Front Immunol. 8:16582017. View Article : Google Scholar : PubMed/NCBI


Cohen JI: Epstein-Barr virus infection. N Engl J Med. 343:481–492. 2000. View Article : Google Scholar : PubMed/NCBI


Crombie JL and LaCasce AS: Epstein Barr Virus associated B-cell lymphomas and iatrogenic lymphoproliferative disorders. Front Oncol. 9:1092019. View Article : Google Scholar : PubMed/NCBI


Chiu YF and Sugden B: Epstein-Barr Virus: The path from latent to productive infection. Annu Rev Virol. 3:359–372. 2016. View Article : Google Scholar : PubMed/NCBI


Kanda T: EBV-encoded latent genes. Adv Exp Med Biol. 1045:377–394. 2018. View Article : Google Scholar : PubMed/NCBI


Yang JH, Sun XS, Xiao BB, Liu LT, Guo SS, Liang JD, Jia GD, Tang LQ, Chen QY and Mai HQ: Subdivision of de-novo metastatic nasopharyngeal carcinoma based on tumor burden and pretreatment EBV DNA for therapeutic guidance of locoregional radiotherapy. BMC Cancer. 21:5342021. View Article : Google Scholar : PubMed/NCBI


He Y, Yang D, Zhou T, Xue W, Zhang J, Li F, Wang F, Wang T, Wu Z, Liao Y, et al: Epstein-Barr virus DNA loads in the peripheral blood cells predict the survival of locoregionally-advanced nasopharyngeal carcinoma patients. Cancer Biol Med. 18:888–899. 2021. View Article : Google Scholar : PubMed/NCBI


Qin JQ, Yin H, Wu JZ, Chen RZ, Xia Y, Wang L, Zhu HY, Fan L, Li JY, Liang JH and Xu W: Pretreatment whole blood Epstein-Barr virus DNA predicts prognosis in Hodgkin lymphoma. Leuk Res. 107:1066072021. View Article : Google Scholar : PubMed/NCBI


Kim JH, Cho H, Sung H, Jung AR, Lee YS, Lee SW, Ryu JS, Chae EJ, Kim KW, Huh J, et al: Reappraisal of the prognostic value of Epstein-Barr virus status in monomorphic post-transplantation lymphoproliferative disorders-diffuse large B-cell lymphoma. Sci Rep. 11:28802021. View Article : Google Scholar : PubMed/NCBI


Xie Y, Wang T and Wang L: Hydroa vacciniforme-like lymphoproliferative disorder: A study of clinicopathology and whole-exome sequencing in Chinese patients. J Dermatol Sci. 99:128–134. 2020. View Article : Google Scholar : PubMed/NCBI


Miyake T, Yamamoto T, Hirai Y, Otsuka M, Hamada T, Tsuji K, Morizane S, Suzuki D, Aoyama Y and Iwatsuki K: Survival rates and prognostic factors of Epstein-Barr virus-associated hydroa vacciniforme and hypersensitivity to mosquito bites. Br J Dermatol. 172:56–63. 2015. View Article : Google Scholar : PubMed/NCBI


Thorley-Lawson DA: EBV persistence-introducing the virus. Curr Top Microbiol Immunol. 390:151–209. 2015.PubMed/NCBI


Gutzeit C, Nagy N, Gentile M, Lyberg K, Gumz J, Vallhov H, Puga I, Klein E, Gabrielsson S, Cerutti A and Scheynius A: Exosomes derived from Burkitt's lymphoma cell lines induce proliferation, differentiation, and class-switch recombination in B cells. J Immunol. 192:5852–5862. 2014. View Article : Google Scholar : PubMed/NCBI


Ito M, Kudo K, Higuchi H, Otsuka H, Tanaka M, Fukunishi N, Araki T, Takamatsu M, Ino Y, Kimura Y and Kotani A: Proteomic and phospholipidomic characterization of extracellular vesicles inducing tumor microenvironment in Epstein-Barr virus-associated lymphomas. FASEB J. 35:e215052021. View Article : Google Scholar : PubMed/NCBI


Young LS and Rickinson AB: Epstein-Barr virus: 40 Years on. Nat Rev Cancer. 4:757–768. 2004. View Article : Google Scholar : PubMed/NCBI


Hurwitz SN, Nkosi D, Conlon MM, York SB, Liu X, Tremblay DC and Meckes DG Jr: CD63 regulates Epstein-Barr Virus LMP1 exosomal packaging, enhancement of vesicle production, and noncanonical NF-κB signaling. J Virol. 91:e02251–16. 2017. View Article : Google Scholar : PubMed/NCBI


Middeldorp JM and Pegtel DM: Multiple roles of LMP1 in Epstein-Barr virus induced immune escape. Semin Cancer Biol. 18:388–396. 2008. View Article : Google Scholar : PubMed/NCBI


Kaye KM, Izumi KM and Kieff E: Epstein-Barr virus latent membrane protein 1 is essential for B-lymphocyte growth transformation. Proc Natl Acad Sci USA. 90:9150–9154. 1993. View Article : Google Scholar : PubMed/NCBI


Nkosi D, Howell LA, Cheerathodi MR, Hurwitz SN, Tremblay DC, Liu X and Meckes DG Jr: Transmembrane domains mediate intra- and extracellular trafficking of Epstein-Barr virus latent membrane protein 1. J Virol. 92:e00280–18. 2018. View Article : Google Scholar : PubMed/NCBI


Rialland P, Lankar D, Raposo G, Bonnerot C and Hubert P: BCR-bound antigen is targeted to exosomes in human follicular lymphoma B-cells. Biol Cell. 98:491–501. 2006. View Article : Google Scholar : PubMed/NCBI


Vallhov H, Gutzeit C, Johansson SM, Nagy N, Paul M, Li Q, Friend S, George TC, Klein E, Scheynius A and Gabrielsson S: Exosomes containing glycoprotein 350 released by EBV-transformed B cells selectively target B cells through CD21 and block EBV infection in vitro. J Immunol. 186:73–82. 2011. View Article : Google Scholar : PubMed/NCBI


Nanbo A, Kawanishi E, Yoshida R and Yoshiyama H: Exosomes derived from Epstein-Barr virus-infected cells are internalized via caveola-dependent endocytosis and promote phenotypic modulation in target cells. J Virol. 87:10334–10347. 2013. View Article : Google Scholar : PubMed/NCBI


Samanta M, Iwakiri D, Kanda T, Imaizumi T and Takada K: EB virus-encoded RNAs are recognized by RIG-I and activate signaling to induce type I IFN. EMBO J. 25:4207–4214. 2006. View Article : Google Scholar : PubMed/NCBI


Nanbo A, Inoue K, Adachi-Takasawa K and Takada K: Epstein-Barr virus RNA confers resistance to interferon-alpha-induced apoptosis in Burkitt's lymphoma. EMBO J. 21:954–965. 2002. View Article : Google Scholar : PubMed/NCBI


Fok V, Friend K and Steitz JA: Epstein-Barr virus noncoding RNAs are confined to the nucleus, whereas their partner, the human La protein, undergoes nucleocytoplasmic shuttling. J Cell Biol. 173:319–325. 2006. View Article : Google Scholar : PubMed/NCBI


Baglio SR, van Eijndhoven MA, Koppers-Lalic D, Berenguer J, Lougheed SM, Gibbs S, Léveillé N, Rinkel RN, Hopmans ES, Swaminathan S, et al: Sensing of latent EBV infection through exosomal transfer of 5′pppRNA. Proc Natl Acad Sci USA. 113:E587–E596. 2016. View Article : Google Scholar : PubMed/NCBI


Burassakarn A, Srisathaporn S, Pientong C, Wongjampa W, Vatanasapt P, Patarapadungkit N and Ekalaksananan T: Exosomes-carrying Epstein-Barr virus-encoded small RNA-1 induces indoleamine 2,3-dioxygenase expression in tumor-infiltrating macrophages of oral squamous-cell carcinomas and suppresses T-cell activity by activating RIG-I/IL-6/TNF-α pathway. Oral Oncol. 117:1052792021. View Article : Google Scholar : PubMed/NCBI


Pratt ZL, Kuzembayeva M, Sengupta S and Sugden B: The microRNAs of Epstein-Barr Virus are expressed at dramatically differing levels among cell lines. Virology. 386:387–397. 2009. View Article : Google Scholar : PubMed/NCBI


Higuchi H, Yamakawa N, Imadome KI, Yahata T, Kotaki R, Ogata J, Kakizaki M, Fujita K, Lu J, Yokoyama K, et al: Role of exosomes as a proinflammatory mediator in the development of EBV-associated lymphoma. Blood. 131:2552–2567. 2018. View Article : Google Scholar : PubMed/NCBI


Haneklaus M, Gerlic M, Kurowska-Stolarska M, Rainey AA, Pich D, McInnes IB, Hammerschmidt W, O'Neill LA and Masters SL: Cutting edge: miR-223 and EBV miR-BART15 regulate the NLRP3 inflammasome and IL-1β production. J Immunol. 189:3795–3799. 2012. View Article : Google Scholar : PubMed/NCBI


Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks BG, Fitzgerald KA, et al: Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol. 183:787–791. 2009. View Article : Google Scholar : PubMed/NCBI


Johnnidis JB, Harris MH, Wheeler RT, Stehling-Sun S, Lam MH, Kirak O, Brummelkamp TR, Fleming MD and Camargo FD: Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature. 451:1125–1129. 2008. View Article : Google Scholar : PubMed/NCBI


Chim CS, Ma SY, Au WY, Choy C, Lie AK, Liang R, Yau CC and Kwong YL: Primary nasal natural killer cell lymphoma: Long-term treatment outcome and relationship with the international prognostic index. Blood. 103:216–221. 2004. View Article : Google Scholar : PubMed/NCBI


Lee JH, Choi J, Ahn YO, Kim TM and Heo DS: CD21-independent Epstein-Barr virus entry into NK cells. Cell Immunol. 327:21–25. 2018. View Article : Google Scholar : PubMed/NCBI


Ahmed W, Philip PS, Attoub S and Khan G: Epstein-Barr virus-infected cells release Fas ligand in exosomal fractions and induce apoptosis in recipient cells via the extrinsic pathway. J Gen Virol. 96:3646–3659. 2015. View Article : Google Scholar : PubMed/NCBI


Chuang YC, Hsieh MC, Lin CC, Lo YS, Ho HY, Hsieh MJ and Lin JT: Pinosylvin inhibits migration and invasion of nasopharyngeal carcinoma cancer cells via regulation of epithelial-mesenchymal transition and inhibition of MMP2. Oncol Rep. 46:1432021. View Article : Google Scholar : PubMed/NCBI


Keryer-Bibens C, Pioche-Durieu C, Villemant C, Souquère S, Nishi N, Hirashima M, Middeldorp J and Busson P: Exosomes released by EBV-infected nasopharyngeal carcinoma cells convey the viral latent membrane protein 1 and the immunomodulatory protein galectin 9. BMC Cancer. 6:2832006. View Article : Google Scholar : PubMed/NCBI


Hirashima M, Kashio Y, Nishi N, Yamauchi A, Imaizumi TA, Kageshita T, Saita N and Nakamura T: Galectin-9 in physiological and pathological conditions. Glycoconj J. 19:593–600. 2002. View Article : Google Scholar : PubMed/NCBI


Miller WE and Raab-Traub N: The EGFR as a target for viral oncoproteins. Trends Microbiol. 7:453–458. 1999. View Article : Google Scholar : PubMed/NCBI


Meckes DG Jr, Shair KH, Marquitz AR, Kung CP, Edwards RH and Raab-Traub N: Human tumor virus utilizes exosomes for intercellular communication. Proc Natl Acad Sci USA. 107:20370–20375. 2010. View Article : Google Scholar : PubMed/NCBI


Yang MH and Wu KJ: TWIST activation by hypoxia inducible factor-1 (HIF-1): Implications in metastasis and development. Cell Cycle. 7:2090–2096. 2008. View Article : Google Scholar : PubMed/NCBI


Aga M, Bentz GL, Raffa S, Torrisi MR, Kondo S, Wakisaka N, Yoshizaki T, Pagano JS and Shackelford J: Exosomal HIF1α supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes. Oncogene. 33:4613–4622. 2014. View Article : Google Scholar : PubMed/NCBI


Basilico C and Moscatelli D: The FGF family of growth factors and oncogenes. Adv Cancer Res. 59:115–165. 1992. View Article : Google Scholar : PubMed/NCBI


Ceccarelli S, Visco V, Raffa S, Wakisaka N, Pagano JS and Torrisi MR: Epstein-Barr virus latent membrane protein 1 promotes concentration in multivesicular bodies of fibroblast growth factor 2 and its release through exosomes. Int J Cancer. 121:1494–1506. 2007. View Article : Google Scholar : PubMed/NCBI


Yu H, Lu J, Zuo L, Yan Q, Yu Z, Li X, Huang J, Zhao L, Tang H, Luo Z, et al: Epstein-Barr virus downregulates microRNA 203 through the oncoprotein latent membrane protein 1: A contribution to increased tumor incidence in epithelial cells. J Virol. 86:3088–3099. 2012. View Article : Google Scholar : PubMed/NCBI


Mrizak D, Martin N, Barjon C, Jimenez-Pailhes AS, Mustapha R, Niki T, Guigay J, Pancré V, de Launoit Y, Busson P, et al: Effect of nasopharyngeal carcinoma-derived exosomes on human regulatory T cells. J Natl Cancer Inst. 107:3632014.PubMed/NCBI


Yogev O, Henderson S, Hayes MJ, Marelli SS, Ofir-Birin Y, Regev-Rudzki N, Herrero J and Enver T: Herpesviruses shape tumour microenvironment through exosomal transfer of viral microRNAs. PLoS Pathog. 13:e10065242017. View Article : Google Scholar : PubMed/NCBI


Fan C, Tang Y, Wang J, Xiong F, Guo C, Wang Y, Xiang B, Zhou M, Li X, Wu X, et al: The emerging role of Epstein-Barr virus encoded microRNAs in nasopharyngeal carcinoma. J Cancer. 9:2852–2864. 2018. View Article : Google Scholar : PubMed/NCBI


Lei T, Yuen KS, Xu R, Tsao SW, Chen H, Li M, Kok KH and Jin DY: Targeting of DICE1 tumor suppressor by Epstein-Barr virus-encoded miR-BART3* microRNA in nasopharyngeal carcinoma. Int J Cancer. 133:79–87. 2013. View Article : Google Scholar : PubMed/NCBI


Wang J, Zheng X, Qin Z, Wei L, Lu Y, Peng Q, Gao Y, Zhang X, Zhang X, Li Z, et al: Epstein-Barr virus miR-BART3-3p promotes tumorigenesis by regulating the senescence pathway in gastric cancer. J Biol Chem. 294:4854–4866. 2019. View Article : Google Scholar : PubMed/NCBI


Murphy G, Pfeiffer R, Camargo MC and Rabkin CS: Meta-analysis shows that prevalence of Epstein-Barr virus-positive gastric cancer differs based on sex and anatomic location. Gastroenterology. 137:824–833. 2009. View Article : Google Scholar : PubMed/NCBI


Burke AP, Yen TS, Shekitka KM and Sobin LH: Lymphoepithelial carcinoma of the stomach with Epstein-Barr virus demonstrated by polymerase chain reaction. Mod Pathol. 3:377–380. 1990.PubMed/NCBI


Choi H, Lee H, Kim SR, Gho YS and Lee SK: Epstein-Barr virus-encoded microRNA BART15-3p promotes cell apoptosis partially by targeting BRUCE. J Virol. 87:8135–8144. 2013. View Article : Google Scholar : PubMed/NCBI


Balkwill FR, Capasso M and Hagemann T: The tumor microenvironment at a glance. J Cell Sci. 125:5591–5596. 2012. View Article : Google Scholar : PubMed/NCBI


Hinata M, Kunita A, Abe H, Morishita Y, Sakuma K, Yamashita H, Seto Y, Ushiku T and Fukayama M: Exosomes of Epstein-Barr virus-associated gastric carcinoma suppress dendritic cell maturation. Microorganisms. 8:17762020. View Article : Google Scholar : PubMed/NCBI


Camargo MC, Kim WH, Chiaravalli AM, Kim KM, Corvalan AH, Matsuo K, Yu J, Sung JJ, Herrera-Goepfert R, Meneses-Gonzalez F, et al: Improved survival of gastric cancer with tumour Epstein-Barr virus positivity: An international pooled analysis. Gut. 63:236–243. 2014. View Article : Google Scholar : PubMed/NCBI


Caby MP, Lankar D, Vincendeau-Scherrer C, Raposo G and Bonnerot C: Exosomal-like vesicles are present in human blood plasma. Int Immunol. 17:879–887. 2005. View Article : Google Scholar : PubMed/NCBI


Houali K, Wang X, Shimizu Y, Djennaoui D, Nicholls J, Fiorini S, Bouguermouh A and Ooka T: A new diagnostic marker for secreted Epstein-Barr virus encoded LMP1 and BARF1 oncoproteins in the serum and saliva of patients with nasopharyngeal carcinoma. Clin Cancer Res. 13:4993–5000. 2007. View Article : Google Scholar : PubMed/NCBI


Mao Y, Zhang DW, Zhu H, Lin H, Xiong L, Cao Q, Liu Y, Li QD, Xu JR, Xu LF and Chen RJ: LMP1 and LMP2A are potential prognostic markers of extranodal NK/T-cell lymphoma, nasal type (ENKTL). Diagn Pathol. 7:1782012. View Article : Google Scholar : PubMed/NCBI


Luan X, Yang W, Bai X, Li H, Li H, Fan W, Zhang H, Liu W and Sun L: Cyclophilin A is a key positive and negative feedback regulator within interleukin-6 trans-signaling pathway. FASEB J. 35:e219582021. View Article : Google Scholar : PubMed/NCBI


Liu L, Zuo L, Yang J, Xin S, Zhang J, Zhou J, Li G, Tang J and Lu J: Exosomal cyclophilin A as a novel noninvasive biomarker for Epstein-Barr virus associated nasopharyngeal carcinoma. Cancer Med. 8:3142–3151. 2019. View Article : Google Scholar : PubMed/NCBI


Zhang G, Zong J, Lin S, Verhoeven RJ, Tong S, Chen Y, Ji M, Cheng W, Tsao SW, Lung M, et al: Circulating Epstein-Barr virus microRNAs miR-BART7 and miR-BART13 as biomarkers for nasopharyngeal carcinoma diagnosis and treatment. Int J Cancer. 136:E301–E312. 2015. View Article : Google Scholar : PubMed/NCBI


Wardana T, Gunawan L, Herawati C, Oktriani R, Anwar S, Astuti I, Aryandono T and Mubarika S: Circulation EBV Mir-Bart-7 relating to clinical manifestation in nasopharyngeal carcinoma. Asian Pac J Cancer Prev. 21:2777–2782. 2020. View Article : Google Scholar : PubMed/NCBI


Notarte KI, Senanayake S, Macaranas I, Albano PM, Mundo L, Fennell E, Leoncini L and Murray P: MicroRNA and other non-coding RNAs in Epstein-Barr virus-associated cancers. Cancers (Basel). 13:39092021. View Article : Google Scholar : PubMed/NCBI


De Re V, Caggiari L, De Zorzi M, Fanotto V, Miolo G, Puglisi F, Cannizzaro R, Canzonieri V, Steffan A, Farruggia P, et al: Epstein-Barr virus BART microRNAs in EBV-associated Hodgkin lymphoma and gastric cancer. Infect Agent Cancer. 15:422020. View Article : Google Scholar : PubMed/NCBI


Zhao Y, Liu P, Tan H, Chen X, Wang Q and Chen T: Exosomes as smart nanoplatforms for diagnosis and therapy of cancer. Front Oncol. 11:7431892021. View Article : Google Scholar : PubMed/NCBI


Coulouarn C, Factor VM, Andersen JB, Durkin ME and Thorgeirsson SS: Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties. Oncogene. 28:3526–3536. 2009. View Article : Google Scholar : PubMed/NCBI


Lou G, Song X, Yang F, Wu S, Wang J, Chen Z and Liu Y: Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma. J Hematol Oncol. 8:1222015. View Article : Google Scholar : PubMed/NCBI


Wang J, Jiang Q, Faleti OD, Tsang CM, Zhao M, Wu G, Tsao SW, Fu M, Chen Y, Ding T, et al: Exosomal delivery of antagomirs targeting viral and cellular MicroRNAs synergistically inhibits cancer angiogenesis. Mol Ther Nucleic Acids. 22:153–165. 2020. View Article : Google Scholar : PubMed/NCBI


Pitt JM, Marabelle A, Eggermont A, Soria JC, Kroemer G and Zitvogel L: Targeting the tumor microenvironment: Removing obstruction to anticancer immune responses and immunotherapy. Ann Oncol. 27:1482–1492. 2016. View Article : Google Scholar : PubMed/NCBI


Wang X, Xiang Z, Liu Y, Huang C, Pei Y, Wang X, Zhi H, Wong WH, Wei H, Ng IO, et al: Exosomes derived from Vδ2-T cells control Epstein-Barr virus-associated tumors and induce T cell antitumor immunity. Sci Transl Med. 12:eaaz34262020. View Article : Google Scholar : PubMed/NCBI


Kwon SH, Faruque HA, Kee H, Kim E and Park S: Exosome-based hybrid nanostructures for enhanced tumor targeting and hyperthermia therapy. Colloids Surf B Biointerfaces. 205:1119152021. View Article : Google Scholar : PubMed/NCBI


Babcock GJ, Decker LL, Volk M and Thorley-Lawson DA: EBV persistence in memory B cells in vivo. Immunity. 9:395–404. 1998. View Article : Google Scholar : PubMed/NCBI


Min K, Kim JY and Lee SK: Epstein-Barr virus miR-BART1-3p suppresses apoptosis and promotes migration of gastric carcinoma cells by targeting DAB2. Int J Biol Sci. 16:694–707. 2020. View Article : Google Scholar : PubMed/NCBI


Navari M, Etebari M, De Falco G, Ambrosio MR, Gibellini D, Leoncini L and Piccaluga PP: The presence of Epstein-Barr virus significantly impacts the transcriptional profile in immunodeficiency-associated Burkitt lymphoma. Front Microbiol. 6:5562015. View Article : Google Scholar : PubMed/NCBI


Westhoff Smith D and Sugden B: Potential cellular functions of Epstein-Barr nuclear antigen 1 (EBNA1) of Epstein-Barr virus. Viruses. 5:226–240. 2013. View Article : Google Scholar : PubMed/NCBI


Choy EY, Siu KL, Kok KH, Lung RW, Tsang CM, To KF, Kwong DL, Tsao SW and Jin DY: An Epstein-Barr virus-encoded microRNA targets PUMA to promote host cell survival. J Exp Med. 205:2551–2560. 2008. View Article : Google Scholar : PubMed/NCBI


Chiang AK, Tao Q, Srivastava G and Ho FC: Nasal NK- and T-cell lymphomas share the same type of Epstein-Barr virus latency as nasopharyngeal carcinoma and Hodgkin's disease. Int J Cancer. 68:285–290. 1996. View Article : Google Scholar : PubMed/NCBI


Sakamoto K, Sekizuka T, Uehara T, Hishima T, Mine S, Fukumoto H, Sato Y, Hasegawa H, Kuroda M and Katano H: Next-generation sequencing of miRNAs in clinical samples of Epstein-Barr virus-associated B-cell lymphomas. Cancer Med. 6:605–618. 2017. View Article : Google Scholar : PubMed/NCBI


Tsao SW, Tsang CM and Lo KW: Epstein-Barr virus infection and nasopharyngeal carcinoma. Philos Trans R Soc Lond B Biol Sci. 372:201602702017. View Article : Google Scholar : PubMed/NCBI


Zebardast A, Tehrani SS, Latifi T and Sadeghi F: Critical review of Epstein-Barr virus microRNAs relation with EBV-associated gastric cancer. J Cell Physiol. 236:6136–6153. 2021. View Article : Google Scholar : PubMed/NCBI


Meckes DG Jr, Gunawardena HP, Dekroon RM, Heaton PR, Edwards RH, Ozgur S, Griffith JD, Damania B and Raab-Traub N: Modulation of B-cell exosome proteins by gamma herpesvirus infection. Proc Natl Acad Sci USA. 110:E2925–E2933. 2013. View Article : Google Scholar : PubMed/NCBI


Pei Y, Wong JHY and Robertson ES: Targeted therapies for Epstein-Barr virus-associated lymphomas. Cancers (Basel). 12:25652020. View Article : Google Scholar : PubMed/NCBI


Spender LC, Lucchesi W, Bodelon G, Bilancio A, Karstegl CE, Asano T, Dittrich-Breiholz O, Kracht M, Vanhaesebroeck B and Farrell PJ: Cell target genes of Epstein-Barr virus transcription factor EBNA-2: Induction of the p55alpha regulatory subunit of PI3-kinase and its role in survival of EREB2.5 cells. J Gen Virol. 87:2859–2867. 2006. View Article : Google Scholar : PubMed/NCBI


Ahmed W and Khan G: The labyrinth of interactions of Epstein-Barr virus-encoded small RNAs. Rev Med Virol. 24:3–14. 2014. View Article : Google Scholar : PubMed/NCBI

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Chen W, Xie Y, Wang T and Wang L: New insights into Epstein‑Barr virus‑associated tumors: Exosomes (Review). Oncol Rep 47: 13, 2022
Chen, W., Xie, Y., Wang, T., & Wang, L. (2022). New insights into Epstein‑Barr virus‑associated tumors: Exosomes (Review). Oncology Reports, 47, 13.
Chen, W., Xie, Y., Wang, T., Wang, L."New insights into Epstein‑Barr virus‑associated tumors: Exosomes (Review)". Oncology Reports 47.1 (2022): 13.
Chen, W., Xie, Y., Wang, T., Wang, L."New insights into Epstein‑Barr virus‑associated tumors: Exosomes (Review)". Oncology Reports 47, no. 1 (2022): 13.