Connivance, Complicity, or Collusion? The Role of Noncoding RNAs in Promoting Gammaherpesvirus Tumorigenesis

Abstract

EBV and KSHV are etiologic agents of multiple types of lymphomas and carcinomas. The frequency of EBV⁺ or KSHV⁺ malignancies arising in immunocompromised individuals reflects the intricate evolutionary balance established between these viruses and their immunocompetent hosts. However, the specific mechanisms by which these pathogens drive tumorigenesis remain poorly understood. In recent years an enormous array of cellular and viral noncoding RNAs (ncRNAs) have been discovered, and host ncRNAs have been revealed as contributory factors to every single cancer hallmark cellular process. As new evidence emerges that gammaherpesvirus ncRNAs also alter host processes and viral factors dysregulate host ncRNA expression, and as novel viral ncRNAs continue to be discovered, we examine the contribution of small, non-miRNA ncRNAs and long ncRNAs to gammaherpesvirus tumorigenesis.

Figure 1.. Virus and host ncRNAs are central players in the tumorigenic attributes of gammaherpesviruses.

Gammaherpesviruses promote infection and pathogenesis through (a) utilization of viral ncRNAs that manipulate host cell factors and (b) dysregulation of the expression and stability of host ncRNAs. Viral ncRNAs coordinate interactions with host proteins, DNA and other ncRNAs to alter immune sensing, RNA stability, RNA splicing, transcription, and translation pathways. Such host cell modifications can drive hallmark cancer processes including promoting cell proliferation, blocking apoptosis, and altering immune response networks. Viral miRNAs and proteins can suppress or enhance the expression and stability of specific host nc NAs, including numerous lncRNAs that have already been linked to cancer.