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

Rolf Renne¹  Di Qin²  Wan Li³  Zhiqiang Bai³  Brian J. Krueger³  Jianzhong Zhu³  Qin Yan³  Shou-Jiang Gao⁴  Chun Lu⁴  Weiping Lu⁵  Cong Wang⁶  Minmin Hu⁷ 

[1] Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America;Department of Endocrinology and Metabolism, Huai’an First People’s Hospital, Nanjing Medical University, 6 Beijing Road West, Huai’an, Jiangsu, P. R. China;Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China;Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States of America;Department of Pathology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, P. R. China;Key Laboratory Of Pathogen Biology Of Jiangsu Province, Nanjing Medical University, Nanjing, P. R. China;State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, P. R. China

关键词: Cell migration;    Endothelial cells;    MicroRNAs;    3' UTR;    Infectious disease control;    Kaposi sarcoma;    G protein coupled receptors;    Lentivirus;   

DOI  :  10.1371/journal.ppat.1005171

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY