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.
Highlights
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus associated with Kaposi’s sarcoma (KS) commonly seen in AIDS patients [1]
We demonstrated that miR-K3 promoted cell migration and invasion by directly targeting G protein-coupled receptor (GPCR) kinase 2 (GRK2)
We found that the chemokine receptor CXCR2, which was negatively regulated by G protein-coupled receptor kinase 2 (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
Summary
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus associated with Kaposi’s sarcoma (KS) commonly seen in AIDS patients [1]. The early manifestations of KS usually appear in skin and lymph nodes; advanced KS often behaves as a highly disseminated tumor involved with visceral organs including the respiratory and gastrointestinal tract [5,6]. Among the four distinct clinical variants of KS (classic KS, endemic KS, iatrogenic KS and AIDS-KS), AIDS-KS is the most common and aggressive form and frequently occurs throughout the body, including skin of the face, torso, mucous membranes of the oral cavity, the respiratory tract, lungs and intestines [7]. Distal dissemination or metastasis is often observed in KS and AIDS-KS patients and causes diffuse lung disease, such as pulmonary KS. Understanding of the molecular basis underlying KS tumor dissemination could shed lights on the mechanism of AIDS-KS pathogenesis and lead to the development of rational therapies
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