title: The SH3BGR/STAT3 Pathway Regulates Cell Migration and Angiogenesis Induced by a Gammaherpesvirus MicroRNA.
abstract: Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is a gammaherpesvirus etiologically associated with KS, a highly disseminated angiogenic tumor of hyperproliferative spindle endothelial cells. KSHV encodes 25 mature microRNAs but their roles in KSHV-induced tumor dissemination and angiogenesis remain unknown. Here, we investigated KSHV-encoded miR-K12-6-3p (miR-K6-3p) promotion of endothelial cell migration and angiogenesis, which are the underlying mechanisms of tumor dissemination and angiogenesis. We found that ectopic expression of miR-K6-3p promoted endothelial cell migration and angiogenesis. Mass spectrometry, bioinformatics and luciferase reporter analyses revealed that miR-K6-3p directly targeted sequence in the 3' untranslated region (UTR) of SH3 domain binding glutamate-rich protein (SH3BGR). Overexpression of SH3BGR reversed miR-K6-3p induction of cell migration and angiogenesis. Mechanistically, miR-K6-3p downregulated SH3BGR, hence relieved STAT3 from SH3BGR direct binding and inhibition, which was required for miR-K6-3p maximum activation of STAT3 and induction of cell migration and angiogenesis. Finally, deletion of miR-K6 from the KSHV genome abrogated its effect on the SH3BGR/STAT3 pathway, and KSHV-induced migration and angiogenesis. Our results illustrated that, by inhibiting SH3BGR, miR-K6-3p enhances cell migration and angiogenesis by activating the STAT3 pathway, and thus contributes to the dissemination and angiogenesis of KSHV-induced malignancies.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, People's Republic of China.|Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, People's Republic of China.|Department of Microbiology, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Wan
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yan
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Xiangya
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Chenyou
authors.initials: C
authors.lastname: Shen
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Minmin
authors.initials: M
authors.lastname: Hu
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: Ying
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Di
authors.initials: D
authors.lastname: Qin
authors.affiliation: Department of Obstetrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Lu
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, People's Republic of China.|Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, People's Republic of China.|Department of Microbiology, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Chun
authors.initials: C
authors.lastname: Lu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000502:physiology; D019288:Herpesvirus 8, Human / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs; D018613:Microscopy, Confocal; D009124:Muscle Proteins / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012367:RNA, Viral; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection
chemical_list: D035683:MicroRNAs; D009124:Muscle Proteins; D012367:RNA, Viral; C104671:SH3BGR protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human