PLoS Pathogens | |
The SH3BGR/STAT3 Pathway Regulates Cell Migration and Angiogenesis Induced by a Gammaherpesvirus MicroRNA | |
Xiangya Ding1  Minmin Hu1  Chenyou Shen1  Ying Zhu1  Brian J. Krueger1  Di Qin1  Shou-Jiang Gao2  Chun Lu2  Hongmei Lu3  Rolf Renne4  Qin Yan5  Wan Li6  | |
[1] Department of Microbiology, Nanjing Medical University, Nanjing, People’s Republic of China;Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States of America;Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America;Department of Obstetrics, The First Affiliated Hospital of 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;State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, People’s Republic of China | |
关键词: Angiogenesis; Cell migration; Endothelial cells; MicroRNAs; 3' UTR; Phosphorylation; Lentivirus; Kaposi sarcoma; | |
DOI : 10.1371/journal.ppat.1005605 | |
学科分类:生物科学(综合) | |
来源: Public Library of Science | |
【 摘 要 】
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.
【 授权许可】
CC BY
【 预 览 】
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