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Marek's Disease Virus-Encoded Analog of Microrna-155 Activates the Oncogene C-Myc by Targeting LTBP1 and Suppressing the TGF-Β Signaling Pathway

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Marek's Disease Virus-Encoded Analog of Microrna-155 Activates the Oncogene C-Myc by Targeting LTBP1 and Suppressing the TGF-Β Signaling Pathway Virology 476 (2015) 72–84 Contents lists available at ScienceDirect Virology journal homepage: www.elsevier.com/locate/yviro Marek's disease virus-encoded analog of microRNA-155 activates the oncogene c-Myc by targeting LTBP1 and suppressing the TGF-β signaling pathway Jia-Qi Chi a,b,c, Man Teng b, Zu-Hua Yu a,b,1, Hui Xu d, Jing-Wei Su b,c, Pu Zhao b,c, Guang-Xu Xing b, Hong-De Liang c, Rui-Guang Deng b, Liang-Hu Qu d, Gai-Ping Zhang c,e,nn, Jun Luo b,n a College of Animal Science and Veterinary Medicine, Jilin University, Changchun 130062, People's Republic of China b Key Laboratory of Animal Immunology of the Ministry of Agriculture, Henan Provincial Key Laboratory of Animal Immunology, Henan Academy of Agricultural Sciences, Zhengzhou 450002, People's Republic of China c College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou 450002, People's Republic of China d Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Science, Sun Yat-Sen (Zhongshan) University, Guangzhou 510275, People's Republic of China e Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, People's Republic of China article info abstract Article history: Marek's disease virus (MDV) is a representative alpha herpes virus able to induce rapid-onset T-cell Received 10 September 2014 lymphoma in its natural host and regarded as an ideal model for the study of virus-induced Returned to author for revisions tumorigenesis. Recent studies have shown that the mdv1-miR-M4-5p, a viral analog of cellular miR- 10 October 2014 155, is critical for MDV's oncogenicity. However, the precise mechanism whereby it was involved in MD Accepted 24 November 2014 lymphomagenesis remained unknown. We have presently identified the host mRNA targets of mdv1- miR-M4-5 and identified the latent TGF-β binding protein 1 (LTBP1) as a critical target for it. We found Keywords: that during MDV infection, down-regulation of LTBP1 expression by mdv1-miR-M4-5p led to a MicroRNA significant decrease of the secretion and activation of TGF-β1, with suppression of TGF-β signaling and MDV a significant activation of expression of c-Myc, a well-known oncogene which is critical for virus-induced miR-155 tumorigenesis. Our findings reveal a novel and important mechanism of how mdv1-miR-M4-5p mdv1-miR-M4-5p LTBP1 potentially contributes to MDV-induced tumorigenesis. TGF-β signaling & 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND Oncogenesis license (http://creativecommons.org/licenses/by-nc-nd/3.0/). Introduction and Griffiths-Jones, 2011; Kincaid and Sullivan, 2012). Previous research on herpes virus-encoded miRNAs had demonstrated their MicroRNAs (miRNAs) are a class of small, 22–24 nt-long, non- potential contributions to the control of latency/lytic activity, coding RNAs (ncRNAs) that play important biological roles by the immune evasion, cell survival, proliferation, and oncogenic cap- regulation of gene expression post-transcriptionally (Bartel, 2004). abilities of these viruses (Boss et al., 2009). Marek's disease virus In the last decade, a large numbers of miRNAs had been identified (MDV) is an avian pathogenic alpha-herpes virus (Davison et al., in diverse virus families, in particular in herpes viruses (Kozomara 2009), which has a double-stranded DNA genomic structure similar to Herpes simplex virus (HSV, an alpha-herpes virus) but infects lymphocytes and behaves biologically more like Epstein–Barr virus n Correspondence to: Key Laboratory of Animal Immunology of the Ministry of (EBV, a gamma-herpes virus), particularly with its ability to induce Agriculture, Henan Academy of Agricultural Sciences, No.116 Huayuan Road, T-cell lymphoma (Ross, 1999). All three serotypes of MDV, MDV-1 Zhengzhou 450002, People’s Republic of China. Tel.: þ86 371 65756056; fax: þ86 371 65738179. (Gallid herpesvirus 2, GaHV2), MDV-2 (Gallid herpesvirus 3, GaHV3) nn Corresponding author at: College of Animal Science and Veterinary Medicine, and herpesvirus of turkeys (HVT) (Meleagrid herpesvirus 1, MeHV1), Henan Agricultural University, No. 63 Nongye Road, Zhengzhou 450002, People's encode miRNAs in the long or short repeat (RL/RS) regions of their Republic of China. Tel.: þ86 371 63550369; fax: þ86 371 63558998. genomes (Burnside et al., 2006; Yao et al., 2007, 2008, 2009; E-mail addresses: [email protected] (J. Luo), Waidner et al., 2009). Although MDV-encoded miRNAs do not show [email protected] (G.-P. Zhang). 1 Present address: College of Animal Science and Technology, Henan University sequence conservation their highly conserved genomic location in of Science and Technology, Luoyang 471003, People's Republic of China. repeat regions implies that they may have specific functions. http://dx.doi.org/10.1016/j.virol.2014.11.027 0042-6822/& 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). J.-Q. Chi et al. / Virology 476 (2015) 72–84 73 In MDV-1 genomes, the viral miRNAs are concentrated in three dual luciferase reporter assay (DLRA). For the first round of DLRA gene clusters, namely the Meq-cluster, the mid-cluster, and the analysis, the vector expressing mdv1-miR-M4-5p (pcDNA6. LAT-cluster (Luo et al., 2010), with their transcription driven by 2-mdv1-miR-M4-5p) was co-transfected in the 293T cells with different promoters (Stik et al., 2010; Coupeau et al., 2012). Most of psiCHECK-2 derived reporter vectors containing the 30-UTRs of the MDV-1 miRNAs are expressed at higher levels in splenic LTBP1, CCR7 and MMP-13 respectively, and then the relative tumors and virally-transformed T-lymphoma cell lines than in luciferase activities were calculated as indicated. As demonstrated virus-infected chicken embryo fibroblast (CEF) (Burnside et al., in Fig. 1a, all three 30-UTR reporters were significantly repressed by 2006; Yao et al., 2008). However, the in vivo expression profiles of mdv1-miR-M4-5p, compared to the negative control miR-neg these miRNAs during different phases of the developing disease (po0.01). To ensure that the down-regulation of targets by suggest that they may have different regulatory roles in MD mdv1-miR-M4-5p is seed sequence dependent, a specific mutant pathogenesis (Luo et al., 2011). Although among oncogenic MDV- vector of pcDNA6.2-mut-mdv1-miR-M4-5p, as shown on the left 1 strains of differing virulence the sequences of miRNA are highly side in Fig. 1 b–d, was constructed. Then, the second round of conserved, the Meq-clustered miRNAs are expressed at higher DLRA analysis were performed and demonstrated that when the levels in lymphomas produced by very virulent plus (vvþ)MDV seed sequence of mdv1-miR-M4-5p was mutated (mut-mdv than those produced by a very virulent (vv) MDV strain, whereas 1-miR-M4-5p), the repression effect on reporters was lost the LAT-clustered miRNAs expression is equal (Morgan et al., (Fig. 1b–d, black columns). To confirm that the repression by 2008), implying that the Meq-clustered miRNAs may have a mdv1-miR-M4-5p on the 30-UTR reporters specifically depended significant role in MDV virulence and oncogenesis. on the predicated binding sites, we further generated mutant The miRNA mdv1-miR-M4-5p, located in the Meq-cluster, is 30-UTR reporters (mut-LTBP1-30-UTR, mut-CCR7-30-UTR and mut- one of the highest expressed MDV-1 miRNAs (Burnside et al., MMP13-30-UTR) and performed reporter assays again as above. As 2006; Yao et al., 2008; Luo et al., 2011). It has been characterized expected, all mutant sites lost their response to mdv1-miR-M4-5p as a virus-encoded functional analog of eukaryotic cellular miR- (Fig. 1 b–d, gray columns), indicating the specificity of the repression. 155 (Zhao et al., 2009) which specifically inhibits the translation of viral proteins involved in the cleavage/packaging of herpesvirus mdv1-miR-M4-5p down-regulates the mRNA level of target gene DNA (Muylkens et al., 2010). Since miR-155 is a host-encoded LTBP1 in the infected cells multifunctional miRNA associated with several cancers and regarded as an oncogene (Tam and Dahlberg, 2006; Faraoni The qRT-PCR analysis showed that, as demonstrated in Fig. 2a, et al., 2009; Tili et al., 2009; Higgs and Slack, 2013; Kong et al., over-expression of mdv1-miR-M4-5p in CEFs significantly reduced 2014), mdv1-miR-M4-5p was hypothesized to play a potential role the mRNA expressions of all the three candidate genes at 24 and in MDV oncogenesis. Recent studies have demonstrated a direct 48 hpi (hour post-infection), but mutant mdv1-miR-M4-5p did critical involvement of mdv1-miR-M4-5p in the MD lymphoma- not. Subsequently, the intracellular miRNA/mRNA target interac- genesis. The deletion of mdv1-miR-M4-5p from the viral genome tions were examined by an MDV de novo infection of CEFs using of the virulent (v) MDV strain pRB-1B5 abolished the oncogenicity the parental virus GX0101 or its mutant GXΔmiR-M4, in which the of the virus (Zhao et al., 2011) whereas for vvMDV strain GX0101, mdv1-miR-M4-5p had been previously deleted from the viral compared to the parent virus, mortality of the mutant was genome (Yu et al., 2014). Post-infection, the characteristic MDV reduced from 100% to 18%, coupled with the gross tumor incidence plaques were visible but very small at 48 hpi, enlarged and spread reduction from 28% to 22% (Yu et al., 2014).
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