A KSHV microRNA Directly Targets G Protein-Coupled Receptor Kinase 2 to Promote the Migration and Invasion of Endothelial Cells by Inducing CXCR2 and Activating AKT Signaling

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Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS). KS is a highly disseminated tumor often involved with visceral organs. Experimentally, KSHV infection induces the invasiveness of endothelial cells. KSHV encodes twelve precursor miRNAs (pre-miRNAs), which are processed into at least 25 mature miRNAs. However, the roles of these miRNAs in KSHV-induced tumor dissemination remain unknown. Here, we investigated KSHV-encoded miR-K12-3 (miR-K3) promotion of endothelial cell migration and invasion, which are the underlying mechanisms of tumor dissemination. We demonstrated that miR-K3 promoted cell migration and invasion by directly targeting G protein-coupled receptor (GPCR) kinase 2 (GRK2). Furthermore, we found that the chemokine receptor CXCR2, which was negatively regulated by GRK2, and its downstream AKT signaling positively mediated miR-K3-induced cell migration and invasion. miR-K3 downregulation of GRK2 relieved its direct inhibitory effect on AKT, and 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. These results show that miR-K3 and its the downstream pathway may be potential therapeutic targets for the treatment of KSHV-associated malignancies.

Vyšlo v časopise: A KSHV microRNA Directly Targets G Protein-Coupled Receptor Kinase 2 to Promote the Migration and Invasion of Endothelial Cells by Inducing CXCR2 and Activating AKT Signaling. PLoS Pathog 11(9): e32767. doi:10.1371/journal.ppat.1005171
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005171

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