title: 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.
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.
authors.affiliation: 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.
authors.forename: X
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Medical School, Quzhou College of Technology, Quzhou, PR China.
authors.forename: S
authors.initials: S
authors.lastname: Yao
authors.affiliation: Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, PR China.
authors.forename: Q
authors.initials: Q
authors.lastname: Yan
authors.affiliation: Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, PR China.
authors.forename: M
authors.initials: M
authors.lastname: Xue
authors.affiliation: Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, PR China.
authors.forename: T
authors.initials: T
authors.lastname: Hao
authors.affiliation: Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, PR China.
authors.forename: F
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, PR China.
authors.forename: D
authors.initials: D
authors.lastname: Qin
authors.affiliation: 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.
authors.forename: C
authors.initials: C
authors.lastname: Lu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D063646:Carcinogenesis / Q000378:metabolism; D002460:Cell Line; D019288:Herpesvirus 8, Human / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000821:virology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000378:metabolism* / Q000821:virology; D015398:Signal Transduction / Q000502:physiology; D014764:Viral Proteins / Q000378:metabolism*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D014764:Viral Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; D051057:Proto-Oncogene Proteins c-akt