title: MiRNA-891a-5p mediates HIV-1 Tat and KSHV Orf-K1 synergistic induction of angiogenesis by activating NF-κB signaling.
abstract: Co-infection with HIV-1 and Kaposi's sarcoma-associated herpesvirus (KSHV) is the cause of aggressive AIDS-related Kaposi's sarcoma (AIDS-KS) characterized by abnormal angiogenesis. The impact of HIV-1 and KSHV interaction on the pathogenesis and extensive angiogenesis of AIDS-KS remains unclear. Here, we explored the synergistic effect of HIV-1 Tat and KSHV oncogene Orf-K1 on angiogenesis. Our results showed that soluble Tat or ectopic expression of Tat enhanced K1-induced cell proliferation, microtubule formation and angiogenesis in chorioallantoic membrane and nude mice models. Mechanistic studies revealed that Tat promoted K1-induced angiogenesis by enhancing NF-κB signaling. Mechanistically, we showed that Tat synergized with K1 to induce the expression of miR-891a-5p, which directly targeted IκBα 3' untranslated region, leading to NF-κB activation. Consequently, inhibition of miR-891a-5p increased IκBα level, prevented nuclear translocation of NF-κB p65 and ultimately suppressed the synergistic effect of Tat- and K1-induced angiogenesis. Our results illustrate that, by targeting IκBα to activate the NF-κB pathway, miR-891a-5p mediates Tat and K1 synergistic induction of angiogenesis. Therefore, the miR-891a-5p/NF-κB pathway is important in the pathogenesis of AIDS-KS, which could be an attractive therapeutic target for AIDS-KS.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, P.R. China Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, P.R. China Department of Microbiology, Nanjing Medical University, Nanjing 210029, P.R. China Medical School, Quzhou College of Technology, Quzhou 324000, P.R. China.
authors.forename: Shuihong
authors.initials: S
authors.lastname: Yao
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing 210029, P.R. China.
authors.forename: Minmin
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Medical Laboratory, The Affiliated Hospital of Xuzhou Medical College, Xuzhou 221000, P.R. China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Hao
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing 210029, P.R. China.
authors.forename: Wan
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing 210029, P.R. China.
authors.forename: Xue
authors.initials: X
authors.lastname: Xue
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing 210029, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Xue
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing 210029, P.R. China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing 210029, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing 210029, P.R. China.
authors.forename: Di
authors.initials: D
authors.lastname: Qin
authors.affiliation: Department of Microbiology, Nanjing Medical University, Nanjing 210029, P.R. China yanqin@njmu.edu.cn.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yan
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Shou-Jiang
authors.initials: SJ
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, P.R. China Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, P.R. China Department of Microbiology, Nanjing Medical University, Nanjing 210029, P.R. China clu@njmu.edu.cn.
authors.forename: Chun
authors.initials: C
authors.lastname: Lu
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D002642:Chick Embryo; D015497:HIV-1; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D008870:Microtubules / Q000648:ultrastructure; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D015398:Signal Transduction; D014759:Viral Envelope Proteins / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*; D014764:Viral Proteins
chemical_list: D020672:I-kappa B Proteins; D008565:Membrane Proteins; D035683:MicroRNAs; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D014759:Viral Envelope Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C111600:K1 protein, Human herpesvirus 8; D014764:Viral Proteins