title: MicroRNA-203 enhances coxsackievirus B3 replication through targeting zinc finger protein-148.
abstract: Coxsackievirus B3 (CVB3) is the primary causal agent of viral myocarditis. During infection, it hijacks host genes to favour its own replication. However, the underlying mechanism is still unclear. Although the viral receptor is an important factor for viral infectivity, other factors such as microRNAs (miRNA) may also play an essential role in its replication after host cell entry. miRNAs are post-transcriptional gene regulators involved in various fundamental biological processes as well as in diseases. To identify miRNAs involved in CVB3 pathogenesis, we performed microarray analysis of miRNAs using CVB3-infected murine hearts and identified miR-203 as one of the most upregulated candidates. We found that miR-203 upregulation is through the activation of protein kinase C/transcription factor AP-1 pathway. We further identified zinc finger protein-148 (ZFP-148), a transcription factor, as a novel target of miR-203. Ectopic expression of miR-203 downregulated ZFP-148 translation, increased cell viability and subsequently enhanced CVB3 replication. Silencing of ZFP-148 by siRNA showed similar effects on CVB3 replication. Finally, analyses of the signalling cascade downstream of ZFP-148 revealed that miR-203-induced suppression of ZFP-148 differentially regulated the expression of prosurvival and proapoptotic genes of the Bcl-2 family proteins as well as the cell cycle regulators. This altered gene expression promoted cell survival and growth, which provided a favourable environment for CVB3 replication, contributing to the further damage of the infected cells. Taken together, this study identified a novel target of miR-203 and revealed, for the first time, the molecular link between miR-203/ZFP-148 and the pathogenesis of CVB3.
authors: Department of Pathology and Laboratory Medicine, The James Hogg Research Center, The Institute for Heart and Lung Health, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada.
authors: Maged Gomaa
authors: MG
authors: Hemida
authors: Xin
authors: X
authors: Ye
authors: Huifang M
authors: HM
authors: Zhang
authors: Paul J
authors: PJ
authors: Hanson
authors: Zhen
authors: Z
authors: Liu
authors: Bruce M
authors: BM
authors: McManus
authors: Decheng
authors: D
authors: Yang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D003384:Coxsackievirus Infections / Q000235:genetics / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D029822:Enterovirus B, Human / Q000472:pathogenicity / Q000502:physiology*; D005786:Gene Expression Regulation; D019254:Genes, bcl-2; D006321:Heart / Q000821:virology; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000378:metabolism*; D009205:Myocarditis / Q000821:virology*; D020411:Oligonucleotide Array Sequence Analysis; D011493:Protein Kinase C / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation; D014779:Virus Replication / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C575934:MIRN203 microRNA, mouse; D035683:MicroRNAs; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C491741:Zfp148 protein, mouse; D011493:Protein Kinase C