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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

Hu, M and Wang, C and Li, W and Lu, W and Bai, Z and Qin, D and Yan, Q and Zhu, J and Krueger, BJ and Renne, R and Gao, SJ and Lu, C (2015) 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 Pathogens, 11 (9). ISSN 1553-7366

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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.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Hu, M
Wang, C
Li, W
Lu, W
Bai, Z
Qin, D
Yan, Q
Zhu, J
Krueger, BJ
Renne, R
Gao, SJ
Lu, C
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorDittmer, Dirk P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Centers: Other Centers, Institutes, Offices, or Units > Pittsburgh Cancer Institute
Date: 1 January 2015
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS Pathogens
Volume: 11
Number: 9
DOI or Unique Handle: 10.1371/journal.ppat.1005171
Institution: University of Pittsburgh
Refereed: Yes
ISSN: 1553-7366
Date Deposited: 23 Aug 2016 13:39
Last Modified: 30 Mar 2021 14:56
URI: http://d-scholarship.pitt.edu/id/eprint/28571

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