Abstract
Kaposi's sarcoma (KS) is a highly disseminated angiogenic tumor of endothelial cells linked to infection by Kaposi's sarcoma-associated herpesvirus (KSHV). KSHV encodes more than two dozens of miRNAs but their roles in KSHV-induced tumor dissemination and metastasis remain unknown. Here, we found that ectopic expression of miR-K12-3 (miR-K3) promoted endothelial cell migration and invasion. Bioinformatics and luciferase reporter analyses showed that miR-K3 directly targeted G protein-coupled receptor (GPCR) kinase 2 (GRK2, official gene symbol ADRBK1). Importantly, overexpression of GRK2 reversed miR-K3 induction of cell migration and invasion. Furthermore, the chemokine receptor CXCR2, which was negatively regulated by GRK2, was upregulated in miR-K3-transduced endothelial cells. Knock down of CXCR2 abolished miR-K3-induced cell migration and invasion. Moreover, miR-K3 downregulation of GRK2 relieved its direct inhibitory effect on AKT. Both CXCR2 induction and the release of AKT from GRK2 were required for miR-K3 maximum activation of AKT and induction of cell migration and invasion. Finally, deletion of miR-K3 from the KSHV genome abrogated its effect on the GRK2/CXCR2/AKT pathway and KSHV-induced migration and invasion. Our data provide the first-line evidence that, by repressing GRK2, miR-K3 facilitates cell migration and invasion via activation of CXCR2/AKT signaling, which likely contribute to the dissemination of KSHV-induced tumors.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Movement
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Cells, Cultured
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Endothelium, Vascular / immunology
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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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Enzyme Repression
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G-Protein-Coupled Receptor Kinase 2 / antagonists & inhibitors*
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G-Protein-Coupled Receptor Kinase 2 / genetics
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G-Protein-Coupled Receptor Kinase 2 / metabolism
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Gene Deletion
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Herpesvirus 8, Human / immunology
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Herpesvirus 8, Human / physiology*
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Host-Pathogen Interactions*
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Human Umbilical Vein Endothelial Cells / immunology
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Human Umbilical Vein Endothelial Cells / metabolism
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Human Umbilical Vein Endothelial Cells / pathology
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Human Umbilical Vein Endothelial Cells / virology
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Humans
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MicroRNAs / metabolism*
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Mutation
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Neoplasm Invasiveness
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Proto-Oncogene Proteins c-akt / agonists
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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RNA / metabolism
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RNA Interference
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RNA, Viral / metabolism*
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Receptors, Interleukin-8B / agonists
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Receptors, Interleukin-8B / genetics
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Receptors, Interleukin-8B / metabolism
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Sarcoma, Kaposi / immunology
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Sarcoma, Kaposi / metabolism
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Sarcoma, Kaposi / pathology
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Sarcoma, Kaposi / virology
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Signal Transduction
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Virus Internalization*
Substances
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MicroRNAs
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RNA, Viral
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RNA, recombinant
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Receptors, Interleukin-8B
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Recombinant Proteins
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RNA
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AKT1 protein, human
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Proto-Oncogene Proteins c-akt
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GRK2 protein, human
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G-Protein-Coupled Receptor Kinase 2