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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, Viral / genetics
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Antigens, Viral / metabolism
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Biomarkers / metabolism
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Blotting, Western
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Cadherins / genetics
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Cadherins / metabolism
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Cell Movement*
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Cells, Cultured
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Endothelium, Lymphatic / metabolism
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Endothelium, Lymphatic / pathology*
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Endothelium, Lymphatic / virology
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Endothelium, Vascular / metabolism
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Endothelium, Vascular / pathology*
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Endothelium, Vascular / virology
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Fluorescent Antibody Technique
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Gene Expression Profiling
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Gene Regulatory Networks*
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Herpesvirus 8, Human / pathogenicity*
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Humans
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Immunoenzyme Techniques
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Luciferases / metabolism
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MicroRNAs / genetics*
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Oligonucleotide Array Sequence Analysis
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Proto-Oncogene Protein c-ets-1 / genetics
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Proto-Oncogene Protein c-ets-1 / metabolism
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Proto-Oncogene Protein c-ets-2 / genetics
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Proto-Oncogene Protein c-ets-2 / metabolism
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RNA, Messenger / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Sarcoma, Kaposi / genetics*
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Sarcoma, Kaposi / pathology*
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Sarcoma, Kaposi / virology
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Stem Cells
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Antigens, Viral
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Biomarkers
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Cadherins
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ETS1 protein, human
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ETS2 protein, human
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FAT4 protein, human
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MIRN221 microRNA, human
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MIRN222 microRNA, human
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MIRN31 microRNA, human
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MicroRNAs
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Nuclear Proteins
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Proto-Oncogene Protein c-ets-1
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Proto-Oncogene Protein c-ets-2
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RNA, Messenger
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Tumor Suppressor Proteins
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latency-associated nuclear antigen
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Luciferases