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Oncogene. 2014 Apr 10;33(15):1986-96. doi: 10.1038/onc.2013.136. Epub 2013 Apr 22.

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.

Author information

1
1] State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, PR China [2] Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, PR China [3] Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, PR China [4] Department of Laboratory Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, PR China.
2
Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, PR China.
3
Medical School, Quzhou College of Technology, Quzhou, PR China.
4
Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
5
1] State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, PR China [2] Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, PR China [3] Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, PR China.

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.

PMID:
23604117
DOI:
10.1038/onc.2013.136
[Indexed for MEDLINE]

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