The SH3BGR/STAT3 Pathway Regulates Cell Migration and Angiogenesis Induced by a Gammaherpesvirus MicroRNA

• Published in: PLoS pathogens Vol. 12; no. 4; p. e1005605
• Main Authors: Li, Wan, Yan, Qin, Ding, Xiangya, Shen, Chenyou, Hu, Minmin, Zhu, Ying, Qin, Di, Lu, Hongmei, Krueger, Brian J, Renne, Rolf, Gao, Shou-Jiang, Lu, Chun
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.04.2016; Public Library of Science (PLoS)
• Subjects: Analysis; Angiogenesis; Animals; B cells; Biology and Life Sciences; Blotting, Western; Cell adhesion & migration; Cell cycle; Cell Movement - physiology; Cytokines; Endothelium; Experiments; Gammaherpesvirus; Genomes; Glutamate; Herpesvirus 8, Human - physiology; Human Umbilical Vein Endothelial Cells; Humans; Immunohistochemistry; Immunoprecipitation; Kaposi's sarcoma-associated herpesvirus; Kaposis sarcoma; Kinases; Mass spectrometry; Mediation; Medicine and Health Sciences; Mice; Mice, Nude; MicroRNA; MicroRNAs; Microscopy, Confocal; Muscle Proteins - metabolism; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Polymerase Chain Reaction; Protein binding; Proteins; RNA, Viral; Rodents; Sarcoma; Sarcoma, Kaposi - pathology; Signal Transduction - physiology; STAT3 Transcription Factor - metabolism; Transfection; Tumors; Viral infections; China
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1005605

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.