title: The manipulation of miRNA-gene regulatory networks by KSHV induces endothelial cell motility.
abstract: miRNAs have emerged as master regulators of cancer-related events. miRNA dysregulation also occurs in Kaposi sarcoma (KS). Exploring the roles of KS-associated miRNAs should help to identify novel angiogenesis and lymphangiogenesis pathways. In the present study, we show that Kaposi sarcoma-associated herpesvirus (KSHV), the etiological agent of KS, induces global miRNA changes in lymphatic endothelial cells (LECs). Specifically, the miR-221/miR-222 cluster is down-regulated, whereas miR-31 is up-regulated. Both latent nuclear antigen (LANA) and Kaposin B repress the expression of the miR-221/miR-222 cluster, which results in an increase of endothelial cell (EC) migration. In contrast, miR-31 stimulates EC migration, so depletion of miR-31 in KSHV-transformed ECs reduces cell motility. Analysis of the putative miRNA targets among KSHV-affected genes showed that ETS2 and ETS1 are the downstream targets of miR-221 and miR-222, respectively. FAT4 is one of the direct targets of miR-31. Overexpression of ETS1 or ETS2 alone is sufficient to induce EC migration, whereas a reduction in FAT4 enhances EC motility. Our results show that KSHV regulates multiple miRNA-mRNA networks to enhance EC motility, which eventually contributes to KS progression by promoting the spread of malignant KS progenitor cells. Targeting KSHV-regulated miRNAs or genes might allow the development of novel therapeutic strategies that induce angiogenesis or allow the treatment of pathogenic (lymph)angiogenesis.
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Wu
authors.forename: Tzu-Fang
authors.initials: TF
authors.lastname: Hu
authors.forename: Yu-Chieh
authors.initials: YC
authors.lastname: Chen
authors.forename: Ya-Ni
authors.initials: YN
authors.lastname: Tsai
authors.forename: Yuan-Hau
authors.initials: YH
authors.lastname: Tsai
authors.forename: Cheng-Chung
authors.initials: CC
authors.lastname: Cheng
authors.forename: Hsei-Wei
authors.initials: HW
authors.lastname: Wang
mesh_terms: D000956:Antigens, Viral / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D004729:Endothelium, Lymphatic / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D019288:Herpesvirus 8, Human / Q000472:pathogenicity*; D006801:Humans; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism; D050787:Proto-Oncogene Protein c-ets-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012514:Sarcoma, Kaposi / Q000235:genetics* / Q000473:pathology* / Q000821:virology; D013234:Stem Cells; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000956:Antigens, Viral; D015415:Biomarkers; D015820:Cadherins; D008156:Luciferases; D035683:MicroRNAs; D009687:Nuclear Proteins; D050784:Proto-Oncogene Protein c-ets-1; D050787:Proto-Oncogene Protein c-ets-2; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; C494041:ETS1 protein, human; C494069:ETS2 protein, human; C534294:FAT4 protein, human; C525709:MIR221, human; C525710:MIR222, human; C534612:MIRN31 microRNA, human; C109540:latency-associated nuclear antigen