Noncoding RNAs produced by oncogenic human herpesviruses

Abstract

The two human herpesviruses that are causally associated with cancer are Epstein–Barr virus and Kaposi’s sarcoma-associated herpesvirus (KSHV). Both are lymphocryptoviruses that establish latency in B lymphocytes and persist for the lifetime of the host. EBV and KSHV are both linked to a variety of lymphomas. EBV is also a causative agent or cofactor in epithelial malignancies such as nasopharyngeal carcinoma whereas Kaposi’s sarcoma is of endothelial cell origin. Both viruses encode a limited number of proteins during latent replication that are important for growth transformation and evasion of the immune system. In addition, they express noncoding RNAs during both latent and lytic infection. Many of these RNAs have been highly conserved during evolution and are expressed in a wide variety of clinical settings, suggesting their fundamental importance in the viral life cycle. The function of some of these RNAs such as the nuclear EBV EBER RNAs remains elusive although they are some of the most abundant transcripts produced by each virus. Both EBV and KSHV also have recently been shown to encode and express microRNAs. The study of these viral microRNAs is just beginning although several of their cellular and viral gene targets have been established. Viral microRNAs appear to be involved in both modulation of the immune response as well as oncogenesis. Because each target gene may have many microRNAs acting on its mRNA, and each microRNA may have more than one target, there are likely to be many new discoveries regarding the complex interactions of viral microRNAs and host cell genes.

Epstein-Barr Virus: A Spectrum of Disease from Mononucleosis to Lymphoma

“…LMP1 and LMP2 proteins are expressed in EBV-positive Hodgkin Reed-Sternberg cells and are likely to play a role in the pathogenesis of Hodgkin's lymphoma (7). The role of EBERs and EBV-encoded microRNAs on cellular gene expression may also play auxiliary roles in promoting oncogenesis (8,9). Finally, the role of chronic bacterial and parasitic infection in the pathogenesis of BL remains to be elucidated and is likely to be multifactorial, related not only to higher EBV loads but also to immunosuppression, chronic antigenic stimulation and the presence of increased numbers of EBV-infected cells during GC reactions.…”

Current Knowledge of MicroRNAs and Noncoding RNAs in Virus-Infected Cells

“…EBER1 (167 nt) and EBER2 (172 nt) (see Figure 2B) are generally the most abundant RNAs in EBV-infected cells (8,122). Structural similarities were observed between EBERs and VAI/VAII ncRNAs and, interestingly, the generation of adenoviral mutants, in which VA RNAs were replaced by EBERs, showed that EBERs could substitute for VA RNA function (125,126).…”

“…Moreover, this repository does not include a panoply of recently discovered, small ncRNAs found in living organisms and forming additional classes of gene regulatory RNAs distinct from miRNAs, such as the repeat-associated small interfering RNAs (rasiRNAs) (6), the tiny noncoding RNAs (tncRNAs) (7) and the Piwi-interacting RNAs (piRNAs) (6). Some ncRNAs produced by viruses are hundreds to thousands of nucleotides in length and represent potential regulators of gene expression (8)(9)(10)(11)(12)). …”

“…The expression pattern of the various EBV miRNAs appears to be fairly complex and depends on both the cell type and on the overall expression pattern of the EBV genes (8). For example, the BART miRNA cluster is well expressed during the lytic process and in cells lines derived from NPC, whereas it is less abundant in B-cells transformed in vitro or derived from BL (70).…”

Non-Coding RNAs: A Dynamic and Complex Network of Gene Regulation

“…Long ncRNAs are also involved in genomic imprinting and X-chromosome inactivation. The ncRNAs as described to be produced by some viruses are hundreds to thousands of nucleotides in length and may have the ability to regulate gene expression in favor of the viral genome [121]. There are examples of long and short ncRNAs intersecting with each other and lncRNAs can themselves be host genes for small RNAs, for example H19 is host to microRNA-675 [122].…”