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.

Fig. 1

Interactions between gammaherpesvirus genes, cellular microRNAs, viral microRNAs and host cell genes. Both EBV and KSHV encode miRNAs that target cellular genes. Inhibitory or repressive effects are denoted by orange arrows and activating or inducing effects are shown by green arrows. EBV microRNA BHRF1 mir-3 targets the chemokine CXCL-11. EBV miRNAs may also downregulate EBV genes (LMP1 and DNA polymerase). EBV latent gene products such as LMP1 induce cell miRNAs which inhibit expression of interferon stimulated genes (ISGs) whereas introns from latent EBNA gene transcripts yield BHRF1 miRNAs. EBV latent gene products may also induce elevated levels of cellular mir155. Mir155 and KSHV mirK-12-11 have some cellular targets in common (BACH1 and Fos are shown as examples) but may also have other targets. The KSHV miRNA cluster likely targets arange of cellular genes important in oncogenesis, including thrombospondin 1 (TBHS 1). The full range of gammaherpesvirus microRNA targets remains to be defined as suggested by blue arrows and question marks.