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Synergy between Kaposi's sarcoma-associated herpesvirus (KSHV) vIL-6 and HIV-1 Nef protein in promotion of angiogenesis and oncogenesis: role of the AKT signaling pathway

Oncogene volume 33, pages 1986–1996 (2014)Cite this article

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Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is the cause of Kaposi's sarcoma (KS), which is the most common AIDS-associated malignancy. KS is characterized by neovascularization and spindle cell proliferation. The interaction between HIV-1 and KSHV has a central role in promoting the aggressive manifestations of KS in AIDS patients; however, the pathogenesis underlying AIDS-related KS (AIDS–KS) remains unknown. Herein, we examined the potential of HIV-1 negative factor (Nef) to impact KSHV viral interleukin-6 (vIL-6)-induced angiogenesis and tumorigenesis. In vitro experiments showed that exogenous Nef penetrated vIL-6-expressing endothelial cells. Both internalized and ectopic expression of Nef in endothelial cells and fibroblasts synergized with vIL-6 to promote vascular tube formation and cell proliferation. Using a chicken chorioallantoic membrane (CAM) model, we demonstrated that Nef synergistically promotes vIL-6-induced angiogenesis and tumorigenesis. Animal experiments further showed that Nef facilitates vIL-6-induced angiogenesis and tumor formation in athymic nu/nu mice. Mechanistic studies indicated that Nef synergizes with vIL-6 to enhance angiogenesis and tumorigenesis by activating the AKT pathway in the CAM model, as well as nude mice. LY294002, a specific inhibitor of phosphatidylinositol-3-kinase (PI3K), significantly impaired the ability of Nef to promote vIL-6-induced tumorigenesis in an allograft model of nude mice. Our data provide first-line evidence that Nef may contribute to the pathogenesis underlying AIDS–KS in synergy with vIL-6. These novel findings also suggest that targeting the PI3K/AKT signal may be a potentially effective therapeutic approach in AIDS–KS patients.

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Acknowledgements

This work was supported by grants from the National Basic Research Program of China (973 Program) (2011CB504803), National Natural Science Foundation of China (81171552, 30972619, 30900064, 31270199), the Ph.D Programs Foundation of Ministry of Education of China (20123234110006), Natural Science Foundation of Ministry of Education of Jiangsu Province (great project 10KJA310032 and grant 09KJB310007), Research Fund for the Doctoral Program of Higher Education of China (New Teacher Fund, grant 20093234120004) and China Postdoctoral Science Foundation (2012M511304).

Author Contributions: Conceived and designed the experiments: DQ and CL. Performed the experiments: XZ, YG, SY, QY, MX, TH and FZ. Analyzed the data: XZ, JZ, DQ and CL. Wrote the paper: XZ and CL.

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  1. X Zhu, Y Guo and S Yao: These authors contributed equally to this work.

Authors and Affiliations

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

    X Zhu & C Lu

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

    X Zhu & C Lu

  3. Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, PR China

    X Zhu, Y Guo, Q Yan, M Xue, T Hao, F Zhou, D Qin & C Lu

  4. Department of Laboratory Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, PR China

    X Zhu

  5. Medical School, Quzhou College of Technology, Quzhou, PR China

    S Yao

  6. Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    J Zhu

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Zhu, X., Guo, Y., Yao, S. et al. Synergy between Kaposi's sarcoma-associated herpesvirus (KSHV) vIL-6 and HIV-1 Nef protein in promotion of angiogenesis and oncogenesis: role of the AKT signaling pathway. Oncogene 33, 1986–1996 (2014). https://doi.org/10.1038/onc.2013.136

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