Novel mechanisms of EBV-induced oncogenesis

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Epstein–Barr virus is an etiologic factor in multiple types of cancer that primarily develop in lymphocytes and epithelial cells. The tumors are latently infected yet express distinct subsets of viral proteins that are essential for transformation. The viral oncogenes may be expressed in a subset of cells and are transferred through exosomes to many cells to induce growth and alter the tumor environment. In some of the viral cancers, viral proteins are not expressed, however, the viral miRNAs can alter growth by decreasing expression of negative regulators of cell growth such as tumor suppressors and cellular proteins that induce apoptosis.

Highlights

► Factors that contribute to EBV oncogenesis. ► Variation and reduced viral expression. ► HLA and Immune recognition of viral proteins. ► Growth regulation by miRNAs. ► Exosome transfer of oncogenes and signaling molecules.

Introduction

The Epstein–Barr virus is a fascinating human herpesvirus whose study has provided unique insight into host:pathogen interactions and complex cellular molecular processes. The virus is the first discovered human tumor virus and was initially identified in primary cell cultures of Burkitt lymphoma, an unusual African pediatric lymphoma [1]. The quickly developed serologic studies revealed that most people had antibodies to the virus but that patients with BL had elevated titers to specific antigenic components [2]. The serologic screenings also showed a link between elevated EBV titers and an unusual epithelial nasopharyngeal carcinoma (NPC) that developed with extraordinarily high incidence in Southern China [3]. The seroconversion of the young technician performing these early serologies following a bout with infectious mononucleosis led to definitive serologic studies that proved infectious mononucleosis was the disease manifestation associated with primary infection [4].

The continuing studies of EBV have identified additional cancers and diseases linked to EBV [5]. An overarching goal has been to define in what way a virus that is carried by almost everyone contributes to intriguing and unique cancers. The study of EBV has illuminated the molecular biology of latent herpesvirus infection and new potent mechanisms through which cell growth can be modulated by viruses. This review will summarize key findings that form the basis for our understanding of EBV pathogenesis with special emphasis on newly identified potential mechanisms through which EBV alters cellular growth.

Section snippets

EBV biology and link to human cancers

The biologic properties of the virus were immediately intriguing as it was shown that the cell lines could be established from BL samples and could produce virus that could infect primary B cells with EBV and transform them into immortalized cell lines. This powerful molecular phenotype has led to the identification of the viral proteins that are essential for latent infection and required for cell transformation [6]. Virus production can be induced in the cell lines where most of infected

EBV transformation and viral oncoproteins

Interestingly, differences in viral expression comparing EBV expression in transformed lymphocytes to that in tumor samples were identified in early studies. Comparison of sequences encoding polyadenylated RNA from Burkitt lymphoma biopsy material identified abundant transcription from specific restriction enzyme fragments that was not detected in transformed cell lines [12]. Similar studies of NPC biopsy samples indicated that the sequences later shown to encode EBNA2 and EBNA3 were not

Latent membrane protein 1

Latent membrane protein 1 (LMP1) is considered the major oncogene of EBV as it has transforming properties in cultured cell lines and is essential for B-lymphocyte transformation [5]. LMP1 transcription is also consistently detected in several of the EBV-associated cancers including post-transplant lymphoma, Hodgkin Disease (HD), and nasopharyngeal carcinoma (NPC). LMP1 functions as a constitutively active member of the tumor necrosis factor receptor family and activates multiple signaling

Latent membrane protein 2

The Epstein–Barr virus (EBV) latent membrane protein 2A (LMP2A) is important for maintenance of latency in infected B lymphocytes and also modulates epithelial cell growth [21]. Through its immunoreceptor tyrosine-based activation motif (ITAM) and PY motifs, LMP2A is able to block B cell receptor (BCR) signaling, bind BCR-associated kinases, and manipulate the turnover of itself and these kinases via a PY-mediated interaction with the Nedd4 family of ubiquitin ligases. In B cells, LMP2A

Viral miRNAs

One of the most exciting recent findings in molecular biology has been the identification of microRNAs (miRNAs) that mediate another type of regulation of cellular gene expression [26••]. miRNAs are approximately 22-nucleotide long single stranded RNAs that are closely related to small interfering RNAs (siRNAs) [26••]. It is thought that most miRNAs inhibit the translation of mRNAs by targeting an inhibitory complex to specific mRNAs based on base pair complementarity. The first viral miRNAs to

Conclusions

The molecular studies of EBV transforming proteins have shown them to be a molecular treasure treasure trove that has revealed key regulatory mechanism in critical cell pathways. The EBNA proteins have helped clarify Notch regulated signaling and the properties of the major Notch DNA binding protein, RBPJκ. LMP1 and its interactions with ubiquitin ligases have enabled dissection of NF-κB regulation and led to the identification of canonical, noncanonical, and bcl3 mediated targets. Future

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgement

The summarized studies have been supported by the grants from the National Cancer Institute, CA19014, CA138811, and CA32979 to NR-T

References (38)

  • E. Kieff et al.

    Epstein–Barr virus and its replication

    Field's Virology

    (2001)
  • M. Nonoyama et al.

    Separation of Epstein–Barr virus DNA from large chromosomal DNA in non-virus-producing cells

    Nat New Biol

    (1972)
  • J. Yates et al.

    A cis-acting element from the Epstein–Barr viral genome that permits stable replication of recombinant plasmids in latently infected cells

    Proc Natl Acad Sci U S A

    (1984)
  • J.R. Arrand et al.

    Characterization of the major Epstein–Barr virus-specific RNA in Burkitt lymphoma-derived cells

    J Virol

    (1982)
  • S. Swaminathan et al.

    Recombinant Epstein–Barr virus with small RNA (EBER) genes deleted transforms lymphocytes and replicates in vitro

    Proc Natl Acad Sci U S A

    (1991)
  • N. Raab-Traub et al.

    Epstein–Barr virus transcription in nasopharyngeal carcinoma

    J Virol

    (1983)
  • A. Rickinson et al.

    Epstein–Barr virus and its replication

  • E.S. Robertson et al.

    The amino-terminal domains of Epstein–Barr virus nuclear proteins 3A, 3B, and 3C interact with RBPJ(kappa)

    J Virol

    (1996)
  • T. Henkel et al.

    Mediation of Epstein–Barr virus EBNA2 transactivation by recombination signal-binding protein J kappa

    Science

    (1994)
  • Cited by (0)

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