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