Abstract
MicroRNAs (miRNAs) have been demonstrated for their involvement in virus biology and pathogenesis, including functioning as key determinants of virally-induced cancers. As an important oncogenic α-herpesvirus affecting poultry health, Marek’s disease virus serotype 1 [Gallid alphaherpesvirus 2 (GaHV-2)] induces rapid-onset T-cell lymphomatous disease commonly referred to as Marek’s disease (MD), an excellent biological model for the study of virally-induced cancer in the natural hosts. Previously, we have demonstrated that GaHV-2-encoded miRNAs (especially those within the Meq-cluster) have the potential to act as critical regulators of multiple processes such as virus replication, latency, pathogenesis, and/or oncogenesis. In addition to miR-M4-5p (miR-155 homolog) and miR-M3-5p, we have recently found that miR-M2-5p possibly participate in inducing MD lymphomagenesis. Here, we report the identification of two tumor suppressors, the RNA-binding protein 24 (RBM24) and myogenic differentiation 1 (MYOD1), being two biological targets for miR-M2-5p. Our experiments revealed that as a critical miRNA, miR-M2-5p promotes cell proliferation via regulating the RBM24-mediated p63 overexpression and MYOD1-mediated IGF2 signaling and suppresses apoptosis by targeting the MYOD1-mediated Caspase-3 signaling pathway. Our data present a new strategy of a single viral miRNA exerting dual role to potentially participate in the virally-induced T-cell lymphomagenesis by simultaneously promoting the cell proliferation and suppressing apoptosis.
Highlights
MicroRNAs, a class of small non-coding RNAs in length of 22~24 nucleotides, play important roles in regulating gene expression post-transcriptionally in many biological processes, such as cell development, differentiation, immunoregulation, disease progression, and all aspects of cancer biology (Bartel, 2018; Butz and Patocs, 2019; Mei and Zhang, 2019; Nagy et al, 2019)
To reveal the regulatory mechanisms mediated by GaHV-2encoded miR-M2-5p in Marek’s disease (MD) oncogenesis, a hybrid-PCR was first performed in triplicate to construct a cDNA library for screening the putative host mRNA targets
There were 25 candidate mRNA genes containing the miRNA binding sites in 3'UTRs and 13 of them had perfect base pairing to the seed region of miR-M2-5p, which were further analyzed and predicted as candidate targets utilizing bio-software “RNAhybrid” (Rehmsmeier et al, 2004)
Summary
MicroRNAs (miRNAs), a class of small non-coding RNAs in length of 22~24 nucleotides, play important roles in regulating gene expression post-transcriptionally in many biological processes, such as cell development, differentiation, immunoregulation, disease progression, and all aspects of cancer biology (Bartel, 2018; Butz and Patocs, 2019; Mei and Zhang, 2019; Nagy et al, 2019). The most successful virus species to exploit the miRNA pathway either through regulating host miRNAs or through encoding their own miRNAs to modulate host gene expression, miRNA machinery is beneficial to enhance viral pathogenesis, regulate life cycle switch, immune evasion, and promote the establishment of a reservoir of latently infected cells (Cullen, 2013; Grey, 2015; Piedade and AzevedoPereira, 2016). EBV encodes a total of 44 mature miRNAs. Of which, the miRNAs miR-BART6-3p, miR-BART11-5p, miR-BART2-5p, and miR-BHRF1-2-5p regulate both virus and host gene expressions to play important roles in antiviral immunity, lytic reactivation, and development of cancer (Ross et al, 2013; Albanese et al, 2017; Lu et al, 2017; Chen et al, 2019). Among the 25 KSHV-encoded miRNAs, miR-K12-1, miR-K12-3, and miR-K12-11 have been shown to be critical in lymphoproliferation and viral pathogenesis (Happel et al, 2016; Li et al, 2016; Guo et al, 2017; Qin et al, 2017)
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