A Tiny RNA that Packs a Big Punch: The Critical Role of a Viral miR-155 Ortholog in Lymphomagenesis in Marek’s Disease

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs that have been identified in animals, plants, and viruses. These small RNAs play important roles in post-transcriptional regulation of various cellular processes, including development, differentiation, and all aspects of cancer biology. Rapid-onset T-cell lymphoma of chickens, namely Marek’s disease (MD), induced by Gallid alphaherpesvirus 2 (GaHV2), could provide an ideal natural animal model for herpesvirus-related cancer research. GaHV2 encodes 26 mature miRNAs derived from 14 precursors assembled in three distinct gene clusters in the viral genome. One of the most highly expressed GaHV2 miRNAs, miR-M4-5p, shows high sequence similarity to the cellular miR-155 and the miR-K12-11 encoded by Kaposi’s sarcoma-associated herpesvirus, particularly in the miRNA “seed region.” As with miR-K12-11, miR-M4-5p shares a common set of host and viral target genes with miR-155, suggesting that they may target the same regulatory cellular networks; however, differences in regulatory function between miR-155 and miR-M4-5p may distinguish non-viral and viral mediated tumorigenesis. In this review, we focus on the functions of miR-M4-5p as the viral ortholog of miR-155 to explore how the virus mimics a host pathway to benefit the viral life cycle and trigger virus-induced tumorigenesis.

Efficient Mutagenesis of Marek’s Disease Virus-Encoded microRNAs Using a CRISPR/Cas9-Based Gene Editing System

“…MDV-1 genome expresses a total of 26 mature miRNAs, encoded in 14 precursors as illustrated in Figure 1a, in three gene clusters named as the Meq-, mid-and LAT-clusters within the inverted repeat regions of the genome [8,11,17]. Several MDV-1 miRNAs, such as the viral miR-155 ortholog miR-M4-5p [18][19][20][21][22][23][24], miR-M3-5p [25], and miR-M7-5p [26], have been demonstrated to play key roles in MDV life cycle to regulate herpesvirus DNA cleavage/packaging, latency or especially virally-induced tumorigenesis. While it is known that most of the viral miRNA functions are related to the pathogenicity and/or oncogenicity [27,28], underlying molecular regulatory mechanisms mediated by these tiny RNAs in MDV biology still remain unclear.…”

Latest Insights into Marek’s Disease Virus Pathogenesis and Tumorigenesis

“…Previous research has largely focused on the role of those viral protein-coding genes. However, MDV also encodes a rich repertoire of non-coding RNAs (ncRNAs) including micro RNAs (miRNAs) and a viral telomerase RNA (vTR) [53][54][55][56][57][58][59][60]. vTR shares 88% sequence identity and the conserved stem-loop structure with its cellular homolog in the chicken (cTR) [54].…”

Effect of gga-miR-155 on cell proliferation, apoptosis and invasion of Marek’s disease virus (MDV) transformed cell line MSB1 by targeting RORA

“…Recent studies have identified several host and viral miRNAs that potentially regulate MDVinduced tumorigenesis [14][15][16][17]. MiRNA-155 is a conserved multifunctional cellular miRNA that regulates the proliferation, migration and invasive growth of tumor cells, and is therefore closely associated with tumor initiation and progression [18][19][20][21], Studies show that the MD-encoded miR-M4-5p is the viral ortholog of cellular miR-155, and shares common targets with miR-155 and is involved in MD lymphomagenesis [16,17,22,23]. Zhao et al have implicated the critical role of MDV-miR-M4 in the induction of tumors, demonstrated the similarities function of both orthologs [24].…”