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

PLoS Pathogens

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