title: A KSHV microRNA enhances viral latency and induces angiogenesis by targeting GRK2 to activate the CXCR2/AKT pathway.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). Most tumor cells in these malignancies are latently infected by KSHV. Thus, viral latency is critical for the development of tumor and induction of tumor-associated angiogenesis. KSHV encodes more than two dozens of miRNAs but their roles in KSHV-induced angiogenesis remains unknown. We have recently shown that miR-K12-3 (miR-K3) promoted cell migration and invasion by targeting GRK2/CXCR2/AKT signaling (PLoS Pathog, 2015;11(9):e1005171). Here, we further demonstrated a role of miR-K3 and its induced signal pathway in KSHV latency and KSHV-induced angiogenesis. We found that overexpression of miR-K3 not only promoted viral latency by inhibiting viral lytic replication, but also induced angiogenesis. Further, knockdown of GRK2 inhibited KSHV replication and enhanced KSHV-induced angiogenesis by enhancing the CXCR2/AKT signals. As a result, blockage of CXCR2 or AKT increased KSHV replication and decreased angiogenesis induced by PEL cells in vivo. Finally, deletion of miR-K3 from viral genome reduced KSHV-induced angiogenesis and increased KSHV replication. These findings indicate that the miR-K3/GRK2/CXCR2/AKT axis plays an essential role in KSHV-induced angiogenesis and promotes KSHV latency, and thus may be a potential therapeutic target of KSHV-associated malignancies.
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: Wan
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Gynecology and Obstetrics, Nanjing Maternity and Child Health Hospital Affiliated Hospital of Nanjing Medical University, Nanjing, P. R. China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Jia
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China.
authors.forename: Chenyou
authors.initials: C
authors.lastname: Shen
authors.affiliation: Department of Gynecology and Obstetrics, Nanjing Maternity and Child Health Hospital Affiliated Hospital of Nanjing Medical University, Nanjing, P. R. China.|The Fourth Clinical Medical College of Nanjing Medical University, Nanjing, P. R. China.
authors.forename: Mi
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China.
authors.forename: Jingyun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China.
authors.forename: Yuancui
authors.initials: Y
authors.lastname: Shang
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China.
authors.forename: Kaixiang
authors.initials: K
authors.lastname: Zhu
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China.
authors.forename: Minmin
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yan
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 and Immunology, Eulji University School of Medicine, Daejeon, Republic of Korea.
authors.forename: Myung-Shin
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Obstetrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Krueger
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA.
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, CA, USA.
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: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics / Q000378:metabolism*; D019288:Herpesvirus 8, Human / Q000235:genetics* / Q000472:pathogenicity; D054884:Host-Pathogen Interactions; D006801:Humans; D016393:Lymphoma, B-Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000821:virology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D012367:RNA, Viral / Q000235:genetics*; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D017735:Virus Latency
chemical_list: D035683:MicroRNAs; D012367:RNA, Viral; D023063:Receptors, Interleukin-8B; D051057:Proto-Oncogene Proteins c-akt; C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2
keywords: CXCR2; GRK2; KSHV miRNAs; angiogenesis; latency