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Review
. 2017 Jun 26:8:1169.
doi: 10.3389/fmicb.2017.01169. eCollection 2017.

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

Guoqing Zhuang  1 , Aijun Sun  1 , Man Teng  2 , Jun Luo  2   3
Affiliations
Review

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

Guoqing Zhuang et al. Front Microbiol. .

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.

Keywords: GaHV2; Marek’s disease virus; herpesvirus; miR-155; miR-M4-5p; pathogenesis; tumorigenesis.

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Figures

FIGURE 1
FIGURE 1
Conserved cellular mRNA targets of GaHV2-encoded orthologs of cellular miR-155. (A) miR-M4-5p seed (red) and non-seed (blue) sequences homologous with chicken gga-miR-155. (B) Venn diagram of cellular mRNA targets of both miR-M4-5p and gga-miR-155 involved in different cellular processes with potential relevance to tumorigenesis: (a) and (c) represent miR-M4-5p or gga-miR-155 specific cellular mRNA targets, while (b) represents the shared set of cellular mRNA targets. Adapted from Parnas et al. (2014).
FIGURE 2
FIGURE 2
Schematic of the potential roles of miR-M4-5p and miR-K12-11 in regulating the TGF-β signaling pathway and promoting tumorigenesis. (A) In normal cell metabolism (blue arrows), c-Myc is down regulated by the phosphorylated SMAD2/3 complex, which is induced by LTBP1 binding to its receptor. During GaHV2 infection (red arrows), miR-M4-5p suppresses the expression levels of LTBP1, leading to reduction of the active SMAD2/3 complex, inducing increased expression of c-Myc. The potential combination of c-Myc and the GaHV2-specific oncoprotein, MEQ, promotes cellular transformation. (B) In normal cell metabolism (blue arrows), activated SMAD5 inhibits target gene expression. During KSHV infection (red arrows), miR-K12-11 inhibits the expression of SMAD5. Through abolishing the TGF-β signaling pathway, miR-K12-11 blocks cell cycle arrest to promote cellular transformation. (A,B) are adapted from Chi et al. (2015) and Liu et al. (2012), respectively.
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