title: HIV-1 Nef and KSHV oncogene K1 synergistically promote angiogenesis by inducing cellular miR-718 to regulate the PTEN/AKT/mTOR signaling pathway.
abstract: Kaposi's sarcoma (KS) is an AIDS-defining cancer with aberrant neovascularization caused by KS-associated herpesvirus (KSHV). Although the interaction between HIV-1 and KSHV plays a pivotal role in promoting the aggressive manifestations of KS, the pathogenesis underlying AIDS-KS remains largely unknown. Here we examined HIV-1 Nef protein promotion of KSHV oncoprotein K1-induced angiogenesis. We showed that both internalized and ectopic expression of Nef in endothelial cells synergized with K1 to facilitate vascular tube formation and cell proliferation, and enhance angiogenesis in a chicken CAM model. In vivo experiments further indicated that Nef accelerated K1-induced angiogenesis and tumorigenesis in athymic nu/nu mice. Mechanistic studies revealed that Nef and K1 synergistically activated PI3K/AKT/mTOR signaling by downregulating PTEN. Furthermore, Nef and K1 induced cellular miR-718, which inhibited PTEN expression by directly targeting a seed sequence in the 3' UTR of its mRNA. Inhibition of miR-718 expression increased PTEN synthesis and suppressed the synergistic effect of Nef- and K1-induced angiogenesis and tumorigenesis. These results indicate that, by targeting PTEN, miR-718 mediates Nef- and K1-induced angiogenesis via activation of AKT/mTOR signaling. Our results demonstrate an essential role of miR-718/AKT/mTOR axis in AIDS-KS and thus may represent an attractive therapeutic target.
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 Department of Physiology, Xuzhou Medical College, Xuzhou, Jiangsu 221004, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Xue
authors.affiliation: 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 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: Tingting
authors.initials: T
authors.lastname: Hao
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: Xiaofei
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Obstetrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, P.R. China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Lu
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 clu@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 / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D002642:Chick Embryo; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: C111600:K1 protein, Human herpesvirus 8; C000589574:MIRN718 microRNA, human; D035683:MicroRNAs; D014764:Viral Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase
references.citation: J Virol. 2007 Dec;81(23):12836-45
references.pmid: 17881434
references.citation: Virology. 1997 Sep 15;236(1):147-54
references.pmid: 9299627
references.citation: Neoplasia. 2009 Dec;11(12):1272-84
references.pmid: 20019835
references.citation: Blood. 2007 Mar 1;109(5):2174-82
references.pmid: 17090655
references.citation: Oncogene. 2004 Jul 29;23(34):5770-80
references.pmid: 15235582
references.citation: Nat Rev Cancer. 2010 Oct;10(10):707-19
references.pmid: 20865011
references.citation: J Virol. 2004 Feb;78(4):1918-27
references.pmid: 14747556
references.citation: J Virol. 2012 Nov;86(21):11663-74
references.pmid: 22896623
references.citation: AIDS. 2003 Aug 15;17(12):1847-51
references.pmid: 12891072
references.citation: J Virol. 2012 Nov;86(21):11698-711
references.pmid: 22915806
references.citation: Nat Cell Biol. 2009 Jul;11(7):881-9
references.pmid: 19543271
references.citation: Nat Genet. 2009 Jan;41(1):130-4
references.pmid: 19098914
references.citation: Genes Dev. 2011 Sep 15;25(18):1881-94
references.pmid: 21896651
references.citation: Cancer Res. 2008 Jan 15;68(2):425-33
references.pmid: 18199536
references.citation: Nat Cell Biol. 2010 Feb;12(2):193-9
references.pmid: 20081837
references.citation: Oncogene. 2013 Mar 28;32(13):1651-9
references.pmid: 22614013
references.citation: J Virol. 2014 May;88(9):4987-5000
references.pmid: 24554664
references.citation: J Natl Cancer Inst Monogr. 2001;(28):44-9
references.pmid: 11158206
references.citation: Nat Cell Biol. 2010 May;12(5):513-9
references.pmid: 20418869
references.citation: Cell Res. 2011 May;21(5):793-806
references.pmid: 21221132
references.citation: J Biol Chem. 2008 Nov 28;283(48):33191-8
references.pmid: 18826950
references.citation: Nat Rev Cancer. 2009 Aug;9(8):550-62
references.pmid: 19629070
references.citation: Immunol Rev. 1992 Jun;127:147-55
references.pmid: 1506004
references.citation: Nat Immunol. 2008 Apr;9(4):405-14
references.pmid: 18327259
references.citation: Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):7941-5
references.pmid: 7690138
references.citation: PLoS Pathog. 2007 May 11;3(5):e65
references.pmid: 17500590
references.citation: Nat Rev Cancer. 2002 Jul;2(7):489-501
references.pmid: 12094235
references.citation: J Virol. 2001 Jan;75(2):891-902
references.pmid: 11134302
references.citation: J Natl Cancer Inst. 2002 Jun 19;94(12):926-35
references.pmid: 12072546
references.citation: PLoS Pathog. 2010 Jan 29;6(1):e1000742
references.pmid: 20126446
references.citation: J Virol. 2011 Oct;85(19):9877-86
references.pmid: 21813606
references.citation: Blood. 2013 Jan 17;121(3):499-509
references.pmid: 23223432
references.citation: Oncogene. 2014 Apr 10;33(15):1986-96
references.pmid: 23604117
references.citation: Sci Rep. 2014 Mar 24;4:4450
references.pmid: 24658403
references.citation: World J Gastroenterol. 2013 May 28;19(20):2985-96
references.pmid: 23716978
references.citation: PLoS One. 2013;8(1):e53145
references.pmid: 23301033
references.citation: J Virol. 2008 Sep;82(17):8771-9
references.pmid: 18579585
references.citation: J Infect Dis. 2011 Jun 15;203(12):1824-31
references.pmid: 21606541
references.citation: Int Immunol. 2005 Jul;17(7):879-87
references.pmid: 15908444
references.citation: PLoS Pathog. 2011 Dec;7(12):e1002405
references.pmid: 22174674
references.citation: PLoS Pathog. 2013;9(12):e1003857
references.pmid: 24385912
references.citation: J Acquir Immune Defic Syndr. 2011 Jan 1;56(1):83-90
references.pmid: 21084997
references.citation: AIDS. 1996;10 Suppl A:S51-7
references.pmid: 8883610
references.citation: Nat Cell Biol. 2012 Dec;14(12):1322-9
references.pmid: 23143395
references.citation: Nature. 1987 Nov 19-25;330(6145):266-9
references.pmid: 3118220
references.citation: J Mol Biol. 2011 Jul 29;410(5):1035-51
references.pmid: 21763505
references.citation: J Virol. 2007 Mar;81(5):2401-17
references.pmid: 17151125
references.citation: EMBO Rep. 2010 Oct;11(10):784-90
references.pmid: 20847741
references.citation: EMBO J. 2009 Oct 21;28(20):3067-73
references.pmid: 19779456
references.citation: Am J Hum Genet. 2008 May;82(5):1141-9
references.pmid: 18460397
references.citation: J Pathol. 2011 Nov;225(3):378-89
references.pmid: 21984125
references.citation: FEBS Lett. 1996 Sep 9;393(1):93-6
references.pmid: 8804432
references.citation: J Natl Cancer Inst. 2009 Mar 18;101(6):399-411
references.pmid: 19276446
references.citation: Cancer Lett. 2010 Mar 28;289(2):140-50
references.pmid: 19651473
references.citation: Adv Virol. 2011;2011:
references.pmid: 21625290
references.citation: Nature. 2007 Dec 13;450(7172):1096-9
references.pmid: 18075594
references.citation: Nat Immunol. 2006 Mar;7(3):302-10
references.pmid: 16429138
references.citation: Clin Cancer Res. 2008 Nov 1;14(21):6751-60
references.pmid: 18980968
references.citation: J Virol. 2012 Feb;86(3):1372-81
references.pmid: 22013049
references.citation: PLoS One. 2012;7(11):e49435
references.pmid: 23185331
references.citation: Gastroenterology. 2007 Aug;133(2):647-58
references.pmid: 17681183
references.citation: Cell Cycle. 2007 Feb 15;6(4):438-43
references.pmid: 17329974
references.citation: Biol Res. 2009;42(3):377-89
references.pmid: 19915746
references.citation: Cancer Res. 2006 Apr 1;66(7):3658-66
references.pmid: 16585191
references.citation: Cancer Res. 2004 Apr 15;64(8):2774-81
references.pmid: 15087393
references.citation: Genes Dev. 2009 Jun 1;23(11):1327-37
references.pmid: 19487573
references.citation: Circulation. 1997 Oct 21;96(8):2514-9
references.pmid: 9355887
references.citation: J Virol. 2010 Mar;84(6):2697-706
references.pmid: 20071580
references.citation: Cell Cycle. 2008 Oct;7(20):3143-8
references.pmid: 18843198
references.citation: Virology. 1990 Jun;176(2):413-25
references.pmid: 2111956
references.citation: Genes Dev. 2010 Jan 15;24(2):195-205
references.pmid: 20080955
references.citation: PLoS One. 2013;8(2):e55832
references.pmid: 23418466
references.citation: Am J Respir Crit Care Med. 2006 Aug 15;174(4):437-45
references.pmid: 16728715
references.citation: J Virol. 2014 Jan;88(1):377-92
references.pmid: 24155407
references.citation: PLoS One. 2011 Jan 20;6(1):e16224
references.pmid: 21283761
references.citation: Cell. 1998 May 29;93(5):685-92
references.pmid: 9630214
references.citation: J Virol. 2004 Sep;78(17):9336-42
references.pmid: 15308728
references.citation: Cell. 1991 May 17;65(4):651-62
references.pmid: 2032289
references.citation: Mol Cell. 2010 Aug 27;39(4):493-506
references.pmid: 20797623
references.citation: Cell Host Microbe. 2009 Dec 17;6(6):570-5
references.pmid: 20006845
references.citation: Nat Med. 2001 Nov;7(11):1217-24
references.pmid: 11689886
references.citation: J Biomed Sci. 1998;5(3):203-10
references.pmid: 9678491
references.citation: J Virol. 2010 Dec;84(23):12139-51
references.pmid: 20844036
references.citation: Cancer Res. 1986 Dec;46(12 Pt 1):6333-8
references.pmid: 3022918
references.citation: J Pathol. 2012 Jul;227(3):275-85
references.pmid: 22262409
references.citation: Adv Cancer Res. 2009;102:19-65
references.pmid: 19595306
references.citation: J Virol. 2003 Jul;77(14):8072-86
references.pmid: 12829846
references.citation: AIDS Res Hum Retroviruses. 2011 Feb;27(2):167-78
references.pmid: 20964480
references.citation: J Leukoc Biol. 2010 Jan;87(1):25-34
references.pmid: 20052801
references.citation: J Clin Invest. 1995 Apr;95(4):1723-34
references.pmid: 7535796
references.citation: PLoS One. 2012;7(1):e29770
references.pmid: 22242178
references.citation: Nat Methods. 2007 Sep;4(9):721-6
references.pmid: 17694064
references.citation: Eur J Cancer Prev. 1996 Oct;5(5):410-2
references.pmid: 8972281
references.citation: Science. 1994 Dec 16;266(5192):1865-9
references.pmid: 7997879
references.citation: Cell Cycle. 2014;13(5):845-58
references.pmid: 24419204
references.citation: Cell Host Microbe. 2009 Apr 23;5(4):376-85
references.pmid: 19380116
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4218-23
references.pmid: 20142475