title: 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.
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.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, P. R. China; Key Laboratory Of Pathogen Biology Of Jiangsu Province, Nanjing Medical University, Nanjing, P. R. China; Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China.
authors.forename: Minmin
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Pathology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, P. R. China.
authors.forename: Cong
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China.
authors.forename: Wan
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Endocrinology and Metabolism, Huai'an First People's Hospital, Nanjing Medical University, 6 Beijing Road West, Huai'an, Jiangsu, P. R. China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Bai
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China.
authors.forename: Di
authors.initials: D
authors.lastname: Qin
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yan
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Krueger
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Rolf
authors.initials: R
authors.lastname: Renne
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Shou-Jiang
authors.initials: SJ
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, P. R. China; Key Laboratory Of Pathogen Biology Of Jiangsu Province, Nanjing Medical University, Nanjing, P. R. China; Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China.
authors.forename: Chun
authors.initials: C
authors.lastname: Lu
mesh_terms: D002465:Cell Movement; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D004794:Enzyme Repression; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D019288:Herpesvirus 8, Human / Q000276:immunology / Q000502:physiology*; D054884:Host-Pathogen Interactions; D061307:Human Umbilical Vein Endothelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D009154:Mutation; D009361:Neoplasm Invasiveness; D051057:Proto-Oncogene Proteins c-akt / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D034622:RNA Interference; D012367:RNA, Viral / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012514:Sarcoma, Kaposi / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D015398:Signal Transduction; D053586:Virus Internalization
chemical_list: D035683:MicroRNAs; D012367:RNA, Viral; C039919:RNA, recombinant; D023063:Receptors, Interleukin-8B; D011994:Recombinant Proteins; D012313:RNA; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2