Oncotarget

Research Papers:

A KSHV microRNA enhances viral latency and induces angiogenesis by targeting GRK2 to activate the CXCR2/AKT pathway

Wan Li, Xuemei Jia, Chenyou Shen, Mi Zhang, Jingyun Xu, Yuancui Shang, Kaixiang Zhu, Minmin Hu, Qin Yan, Di Qin, Myung-Shin Lee, Jianzhong Zhu, Hongmei Lu, Brian J. Krueger, Rolf Renne, Shou-Jiang Gao and Chun Lu _

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Oncotarget. 2016; 7:32286-32305. https://doi.org/10.18632/oncotarget.8591

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Abstract

Wan Li1,2,3,*, Xuemei Jia4,*, Chenyou Shen3, Mi Zhang4,5, Jingyun Xu3, Yuancui Shang3, Kaixiang Zhu3, Minmin Hu3, Qin Yan3, Di Qin3, Myung-Shin Lee6, Jianzhong Zhu7, Hongmei Lu8, Brian J. Krueger9, Rolf Renne9, Shou-Jiang Gao10, Chun Lu1,2,3

1State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, P. R. China

2Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, P. R. China

3Department of Microbiology, Nanjing Medical University, Nanjing, P. R. China

4Department of Gynecology and Obstetrics, Nanjing Maternity and Child Health Hospital Affiliated Hospital of Nanjing Medical University, Nanjing, P. R. China

5The Fourth Clinical Medical College of Nanjing Medical University, Nanjing, P. R. China

6Department of Microbiology and Immunology, Eulji University School of Medicine, Daejeon, Republic of Korea

7Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

8Department of Obstetrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China

9Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA

10Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

*These authors have contributed equally to this work

Correspondence to:

Chun Lu, email: clu@njmu.edu.cn

Keywords: KSHV miRNAs, latency, angiogenesis, GRK2, CXCR2

Received: January 11, 2016    Accepted: March 28, 2016    Published: April 5, 2016

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.


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