KSHV MicroRNAs Mediate Cellular Transformation and Tumorigenesis by Redundantly Targeting Cell Growth and Survival Pathways

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Kaposi's sarcoma-associated herpesvirus (KSHV) is causally linked to several human cancers, including Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease, malignancies commonly found in HIV-infected patients. While KSHV encodes diverse functional products, its mechanism of oncogenesis remains unknown. In this study, we determined the roles KSHV microRNAs (miRs) in cellular transformation and tumorigenesis using a recently developed KSHV-induced cellular transformation system of primary rat mesenchymal precursor cells. A mutant with a cluster of 10 precursor miRs (pre-miRs) deleted failed to transform primary cells, and instead, caused cell cycle arrest and apoptosis. Remarkably, the oncogenicity of the mutant virus was fully restored by genetic complementation with the miR cluster or several individual pre-miRs, which rescued cell cycle progression and inhibited apoptosis in part by redundantly targeting IκBα and the NF-κB pathway. Genomic analysis identified common targets of KSHV miRs in diverse pathways with several cancer-related pathways preferentially targeted. These works define for the first time an essential viral determinant for KSHV-induced oncogenesis and identify NF-κB as a critical pathway targeted by the viral miRs. Our results illustrate a common theme of shared functions with hierarchical order among the KSHV miRs.

Vyšlo v časopise: KSHV MicroRNAs Mediate Cellular Transformation and Tumorigenesis by Redundantly Targeting Cell Growth and Survival Pathways. PLoS Pathog 9(12): e32767. doi:10.1371/journal.ppat.1003857
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003857

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1. MesriEA, CesarmanE, BoshoffC (2010) Kaposi's sarcoma and its associated herpesvirus. Nat Rev Cancer 10 : 707–719.

2. CullenBR (2011) Viruses and microRNAs: RISCy interactions with serious consequences. Genes Dev 25 : 1881–1894.

3. JonesT, YeF, BedollaR, HuangY, MengJ, et al. (2012) Direct and efficient cellular transformation of primary rat mesenchymal precursor cells by KSHV. J Clin Invest 122 : 1076–1081.

4. HanahanD, WeinbergRA (2011) Hallmarks of cancer: the next generation. Cell 144 : 646–674.

5. PanH, ZhouF, GaoSJ (2004) Kaposi's sarcoma-associated herpesvirus induction of chromosome instability in primary human endothelial cells. Cancer Res 64 : 4064–4068.

6. MutluAD, CavallinLE, VincentL, ChiozziniC, ErolesP, et al. (2007) In vivo-restricted and reversible malignancy induced by human herpesvirus-8 KSHV: a cell and animal model of virally induced Kaposi's sarcoma. Cancer Cell 11 : 245–258.

7. YeF, LeiX, GaoSJ (2011) Mechanisms of Kaposi's sarcoma-associated herpesvirus latency and reactivation. Adv Virol 2011 : 193860.

8. GanemD (2010) KSHV and the pathogenesis of Kaposi's sarcoma: listening to human biology and medicine. J Clin Invest 120 : 939–949.

9. FaraziTA, SpitzerJI, MorozovP, TuschlT (2011) miRNAs in human cancer. J Pathol 223 : 102–115.

10. CaiX, LuS, ZhangZ, GonzalezCM, DamaniaB, et al. (2005) Kaposi's sarcoma-associated herpesvirus expresses an array of viral microRNAs in latently infected cells. Proc Natl Acad Sci USA 102 : 5570–5575.

11. PfefferS, SewerA, Lagos-QuintanaM, SheridanR, SanderC, et al. (2005) Identification of microRNAs of the herpesvirus family. Nat Methods 2 : 269–276.

12. SamolsMA, HuJ, SkalskyRL, RenneR (2005) Cloning and identification of a microRNA cluster within the latency-associated region of Kaposi's sarcoma-associated herpesvirus. J Virol 79 : 9301–9305.

13. GrundhoffA, SullivanCS, GanemD (2006) A combined computational and microarray-based approach identifies novel microRNAs encoded by human gamma-herpesviruses. Rna 12 : 733–750.

14. MarshallV, ParksT, BagniR, WangCD, SamolsMA, et al. (2007) Conservation of virally encoded microRNAs in Kaposi's sarcoma–associated herpesvirus in primary effusion lymphoma cell lines and in patients with Kaposi's sarcoma or multicentric Castleman disease. J Infect Dis 195 : 645–659.

15. O'HaraAJ, ChughP, WangL, NettoEM, LuzE, et al. (2009) Pre-micro RNA signatures delineate stages of endothelial cell transformation in Kaposi's sarcoma. PLoS Pathog 5: e1000389.

16. BellareP, GanemD (2009) Regulation of KSHV lytic switch protein expression by a virus-encoded microRNA: an evolutionary adaptation that fine-tunes lytic reactivation. Cell Host Microbe 6 : 570–575.

17. LeiX, BaiZ, YeF, XieJ, KimCG, et al. (2010) Regulation of NF-kappaB inhibitor IkappaBalpha and viral replication by a KSHV microRNA. Nat Cell Biol 12 : 193–199.

18. LuF, StedmanW, YousefM, RenneR, LiebermanPM (2010) Epigenetic regulation of Kaposi's sarcoma-associated herpesvirus latency by virus-encoded microRNAs that target Rta and the cellular Rbl2-DNMT pathway. J Virol 84 : 2697–2706.

19. LiangD, GaoY, LinX, HeZ, ZhaoQ, et al. (2011) A human herpesvirus miRNA attenuates interferon signaling and contributes to maintenance of viral latency by targeting IKKepsilon. Cell Res 21 : 793–806.

20. LinX, LiangD, HeZ, DengQ, RobertsonES, et al. (2011) miR-K12-7-5p encoded by Kaposi's sarcoma-associated herpesvirus stabilizes the latent state by targeting viral ORF50/RTA. PloS One 6: e16224.

21. LuCC, LiZ, ChuCY, FengJ, SunR, et al. (2010) MicroRNAs encoded by Kaposi's sarcoma-associated herpesvirus regulate viral life cycle. EMBO Reports 11 : 784–790.

22. AbendJR, RamalingamD, Kieffer-KwonP, UldrickTS, YarchoanR, et al. (2012) KSHV microRNAs target two components of the TLR/IL-1R signaling cascade, IRAK1 and MYD88, to reduce inflammatory cytokine expression. J Virol 86 : 11663–11674.

23. AbendJR, UldrickT, ZiegelbauerJM (2010) Regulation of tumor necrosis factor-like weak inducer of apoptosis receptor protein (TWEAKR) expression by Kaposi's sarcoma-associated herpesvirus microRNA prevents TWEAK-induced apoptosis and inflammatory cytokine expression. J Virol 84 : 12139–12151.

24. BossIW, NadeauPE, AbbottJR, YangY, MergiaA, et al. (2011) A Kaposi's sarcoma-associated herpesvirus-encoded ortholog of microRNA miR-155 induces human splenic B-cell expansion in NOD/LtSz-scid IL2Rgammanull mice. J Virol 85 : 9877–9886.

25. DahlkeC, MaulK, ChristallaT, WalzN, SchultP, et al. (2012) A microRNA Encoded by Kaposi's sarcoma-associated herpesvirus promotes B-cell expansion in vivo. PloS One 7: e49435.

26. GottweinE, MukherjeeN, SachseC, FrenzelC, MajorosWH, et al. (2007) A viral microRNA functions as an orthologue of cellular miR-155. Nature 450 : 1096–1099.

27. HansenA, HendersonS, LagosD, NikitenkoL, CoulterE, et al. (2010) KSHV-encoded miRNAs target MAF to induce endothelial cell reprogramming. Genes Dev 24 : 195–205.

28. LeiX, ZhuY, JonesT, BaiZ, HuangY, et al. (2012) A KSHV microRNA and its variants target TGF-beta pathway to promote cell survival. J Virol 86 : 11698–11711.

29. LiuY, SunR, LinX, LiangD, DengQ, et al. (2012) Kaposi's sarcoma-associated herpesvirus-encoded microRNA miR-K12-11 attenuates transforming growth factor beta signaling through suppression of SMAD5. J Virol 86 : 1372–1381.

30. NachmaniD, Stern-GinossarN, SaridR, MandelboimO (2009) Diverse herpesvirus microRNAs target the stress-induced immune ligand MICB to escape recognition by natural killer cells. Cell Host Microbe 5 : 376–385.

31. QinZ, FreitasE, SullivanR, MohanS, BacelieriR, et al. (2010) Upregulation of xCT by KSHV-encoded microRNAs facilitates KSHV dissemination and persistence in an environment of oxidative stress. PLoS Pathog 6: e1000742.

32. QinZ, KearneyP, PlaisanceK, ParsonsCH (2010) Pivotal advance: Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded microRNA specifically induce IL-6 and IL-10 secretion by macrophages and monocytes. J Leuk Biol 87 : 25–34.

33. SamolsMA, SkalskyRL, MaldonadoAM, RivaA, LopezMC, et al. (2007) Identification of cellular genes targeted by KSHV-encoded microRNAs. PLoS Pathog 3: e65.

34. SkalskyRL, SamolsMA, PlaisanceKB, BossIW, RivaA, et al. (2007) Kaposi's sarcoma-associated herpesvirus encodes an ortholog of miR-155. J Virol 81 : 12836–12845.

35. SuffertG, MaltererG, HausserJ, ViiliainenJ, FenderA, et al. (2011) Kaposi's sarcoma herpesvirus microRNAs target caspase 3 and regulate apoptosis. PLoS Pathog 7: e1002405.

36. ZiegelbauerJM, SullivanCS, GanemD (2009) Tandem array-based expression screens identify host mRNA targets of virus-encoded microRNAs. Nat Genet 41 : 130–134.

37. ZhouFC, ZhangYJ, DengJH, WangXP, PanHY, et al. (2002) Efficient infection by a recombinant Kaposi's sarcoma-associated herpesvirus cloned in a bacterial artificial chromosome: application for genetic analysis. J Virol 76 : 6185–6196.

38. WirtenbergerM, TchatchouS, HemminkiK, KlaesR, SchmutzlerRK, et al. (2006) Association of genetic variants in the Rho guanine nucleotide exchange factor AKAP13 with familial breast cancer. Carcinogenesis 27 : 593–598.

39. BenderAM, CollierLS, RodriguezFJ, TieuC, LarsonJD, et al. (2010) Sleeping beauty-mediated somatic mutagenesis implicates CSF1 in the formation of high-grade astrocytomas. Cancer Res 70 : 3557–3565.

40. EspinosaI, EdrisB, LeeCH, ChengHW, GilksCB, et al. (2011) CSF1 expression in nongynecological leiomyosarcoma is associated with increased tumor angiogenesis. Am J Pathol 179 : 2100–2107.

41. DuongBN, ElliottS, FrigoDE, MelnikLI, VanhoyL, et al. (2006) AKT regulation of estrogen receptor beta transcriptional activity in breast cancer. Cancer Res 66 : 8373–8381.

42. Bossy-WetzelE, BravoR, HanahanD (1992) Transcription factors junB and c–jun are selectively up-regulated and functionally implicated in fibrosarcoma development. Genes Dev 6 : 2340–2351.

43. WangW, ZhangW, HanY, ChenJ, WangY, et al. (2005) NELIN, a new F-actin associated protein, stimulates HeLa cell migration and adhesion. Biochem Biophys Res Commun 330 : 1127–1131.

44. LinY, PengS, YuH, TengH, CuiM (2012) RNAi-mediated downregulation of NOB1 suppresses the growth and colony-formation ability of human ovarian cancer cells. Med Oncol 29 : 311–317.

45. QinJ, ChenX, XieX, TsaiMJ, TsaiSY (2010) COUP-TFII regulates tumor growth and metastasis by modulating tumor angiogenesis. Proc Natl Acad Sci USA 107 : 3687–3692.

46. LeeS, KangJ, YooJ, GanesanSK, CookSC, et al. (2009) Prox1 physically and functionally interacts with COUP-TFII to specify lymphatic endothelial cell fate. Blood 113 : 1856–1859.

47. KonoshitaT, GascJM, VillardE, TakedaR, SeidahNG, et al. (1994) Expression of PC2 and PC1/PC3 in human pheochromocytomas. Mol Cell Endocrinol 99 : 307–314.

48. AbusninaA, AlhosinM, KeravisT, MullerCD, FuhrmannG, et al. (2011) Down-regulation of cyclic nucleotide phosphodiesterase PDE1A is the key event of p73 and UHRF1 deregulation in thymoquinone-induced acute lymphoblastic leukemia cell apoptosis. Cell Signalling 23 : 152–160.

49. AbbottKL, TroupeK, LeeI, PierceM (2006) Integrin-dependent neuroblastoma cell adhesion and migration on laminin is regulated by expression levels of two enzymes in the O-mannosyl-linked glycosylation pathway, PomGnT1 and GnT-Vb. Exp CellRes 312 : 2837–2850.

50. SmolenGA, SchottBJ, StewartRA, DiederichsS, MuirB, et al. (2007) A Rap GTPase interactor, RADIL, mediates migration of neural crest precursors. Genes Dev 21 : 2131–2136.

51. IzaguirreDI, ZhuW, HaiT, CheungHC, KraheR, et al. (2012) PTBP1-dependent regulation of USP5 alternative RNA splicing plays a role in glioblastoma tumorigenesis. Mol Carcinogenesis 51 : 895–906.

52. DayalS, SparksA, JacobJ, Allende-VegaN, LaneDP, et al. (2009) Suppression of the deubiquitinating enzyme USP5 causes the accumulation of unanchored polyubiquitin and the activation of p53. J Biol Chem 284 : 5030–5041.

53. ViderBZ, ZimberA, ChastreE, PrevotS, GespachC, et al. (1996) Evidence for the involvement of the Wnt 2 gene in human colorectal cancer. Oncogene 12 : 153–158.

54. MatushanskyI, HernandoE, SocciND, MillsJE, MatosTA, et al. (2007) Derivation of sarcomas from mesenchymal stem cells via inactivation of the Wnt pathway. J Clin Invest 117 : 3248–3257.

55. LiuXL, ZhaoD, SunDP, WangY, LiY, et al. (2012) Adenovirus-mediated delivery of CALR and MAGE-A3 inhibits invasion and angiogenesis of glioblastoma cell line U87. J Exp Clin Cancer Res 31 : 8.

56. ChowdhuryS, ChenY, YaoTW, AjamiK, WangXM, et al. (2013) Regulation of dipeptidyl peptidase 8 and 9 expression in activated lymphocytes and injured liver. World J Gastroenterol 19 : 2883–2893.

57. MatheeussenV, WaumansY, MartinetW, Van GoethemS, Van der VekenP, et al. (2013) Dipeptidyl peptidases in atherosclerosis: expression and role in macrophage differentiation, activation and apoptosis. Basic Res Cardiol 108 : 350.

58. XiaoW, WangJ, LiH, GuanW, XiaD, et al. (2013) Fibulin-1 is down-regulated through promoter hypermethylation and suppresses renal cell carcinoma progression. J Urol 190 : 291–301.

59. ChouYY, JengYM, MaoTL (2013) HSD3B1 is a specific trophoblast-associated marker not expressed in a wide spectrum of tumors. Int J Gynecol Cancer 23 : 343–347.

60. BorosK, LacaudG, KouskoffV (2011) The transcription factor Mxd4 controls the proliferation of the first blood precursors at the onset of hematopoietic development in vitro. Exp Hematol 39 : 1090–1100.

61. LiJ, YenC, LiawD, PodsypaninaK, BoseS, et al. (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275 : 1943–1947.

62. YooYA, KimMJ, ParkJK, ChungYM, LeeJH, et al. (2005) Mitochondrial ribosomal protein L41 suppresses cell growth in association with p53 and p27Kip1. Mol Cell Biol 25 : 6603–6616.

63. KimMJ, YooYA, KimHJ, KangS, KimYG, et al. (2005) Mitochondrial ribosomal protein L41 mediates serum starvation-induced cell-cycle arrest through an increase of p21(WAF1/CIP1). Biochem Biophys Res Commun 338 : 1179–1184.

64. TibshiraniR (1996) Regression shrinkage and selection via the lasso. J Royal Statist Soc B 58 : 267–288.

65. GottweinE, CullenBR (2010) A human herpesvirus microRNA inhibits p21 expression and attenuates p21-mediated cell cycle arrest. J Virol 84 : 5229–5237.

66. TiliE, CroceCM, MichailleJJ (2009) miR-155: on the crosstalk between inflammation and cancer. Int Rev Immunol 28 : 264–284.

67. ChaudharyPM, JasminA, EbyMT, HoodL (1999) Modulation of the NF-kappa B pathway by virally encoded death effector domains-containing proteins. Oncogene 18 : 5738–5746.

68. MattaH, ChaudharyPM (2004) Activation of alternative NF-kappa B pathway by human herpes virus 8-encoded Fas-associated death domain-like IL-1 beta-converting enzyme inhibitory protein (vFLIP). Proc Natl Acad Sci USA 101 : 9399–9404.

69. YeFC, ZhouFC, XieJP, KangT, GreeneW, et al. (2008) Kaposi's sarcoma-associated herpesvirus latent gene vFLIP inhibits viral lytic replication through NF-kappaB-mediated suppression of the AP-1 pathway: a novel mechanism of virus control of latency. J Virol 82 : 4235–4249.

70. LiuH, YueD, ChenY, GaoSJ, HuangY (2010) Improving performance of mammalian microRNA target prediction. BMC Bioinformatics 11 : 476.

71. GaoSJ, BoshoffC, JayachandraS, WeissRA, ChangY, et al. (1997) KSHV ORF K9 (vIRF) is an oncogene which inhibits the interferon signaling pathway. Oncogene 15 : 1979–1985.

72. BaisC, SantomassoB, CosoO, ArvanitakisL, RaakaEG, et al. (1998) G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature 391 : 86–89.

73. LeeH, VeazeyR, WilliamsK, LiM, GuoJ, et al. (1998) Deregulation of cell growth by the K1 gene of Kaposi's sarcoma-associated herpesvirus. Nat Med 4 : 435–440.

74. RadkovSA, KellamP, BoshoffC (2000) The latent nuclear antigen of Kaposi's sarcoma-associated herpesvirus targets the retinoblastoma-E2F pathway and with the oncogene Hras transforms primary rat cells. Nat Med 6 : 1121–1127.

75. VerschurenEW, KlefstromJ, EvanGI, JonesN (2002) The oncogenic potential of Kaposi's sarcoma-associated herpesvirus cyclin is exposed by p53 loss in vitro and in vivo. Cancer Cell 2 : 229–241.

76. PrakashO, TangZY, PengX, ColemanR, GillJ, et al. (2002) Tumorigenesis and aberrant signaling in transgenic mice expressing the human herpesvirus-8 K1 gene. J NCI 94 : 926–935.

77. ChughP, MattaH, SchamusS, ZachariahS, KumarA, et al. (2005) Constitutive NF-kappaB activation, normal Fas-induced apoptosis, and increased incidence of lymphoma in human herpes virus 8 K13 transgenic mice. Proc Natl Acad Sci USA 102 : 12885–12890.

78. FakhariFD, JeongJH, KananY, DittmerDP (2006) The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus induces B cell hyperplasia and lymphoma. J Clin Invest 116 : 735–742.

79. KellerSA, SchattnerEJ, CesarmanE (2000) Inhibition of NF-kappaB induces apoptosis of KSHV-infected primary effusion lymphoma cells. Blood 96 : 2537–2542.

80. GuasparriI, KellerSA, CesarmanE (2004) KSHV vFLIP is essential for the survival of infected lymphoma cells. J Exp Med 199 : 993–1003.

81. LiuL, EbyMT, RathoreN, SinhaSK, KumarA, et al. (2002) The human herpes virus 8-encoded viral FLICE inhibitory protein physically associates with and persistently activates the Ikappa B kinase complex. J Biol Chem 277 : 13745–13751.

82. MoorePS, ChangY (2010) Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nature Rev Cancer 10 : 878–889.

83. DiDonatoJA, MercurioF, KarinM (2012) NF-kappaB and the link between inflammation and cancer. Immunol Rev 246 : 379–400.

84. BeauparlantP, KwanI, BitarR, ChouP, KoromilasAE, et al. (1994) Disruption of I kappa B alpha regulation by antisense RNA expression leads to malignant transformation. Oncogene 9 : 3189–3197.

85. CarrascoD, PerezP, LewinA, BravoR (1997) IkappaBalpha overexpression delays tumor formation in v-rel transgenic mice. J Exp Med 186 : 279–288.

86. GottweinE, CaiX, CullenBR (2006) A novel assay for viral microRNA function identifies a single nucleotide polymorphism that affects Drosha processing. J Virol 80 : 5321–5326.

87. GaoSJ, DengJH, ZhouFC (2003) Productive lytic replication of a recombinant Kaposi's sarcoma-associated herpesvirus in efficient primary infection of primary human endothelial cells. J Virol 77 : 9738–9749.

88. GaoSJ, KingsleyL, HooverDR, SpiraTJ, RinaldoCR, et al. (1996) Seroconversion to antibodies against Kaposi's sarcoma-associated herpesvirus-related latent nuclear antigens before the development of Kaposi's sarcoma. N Engl J Med 335 : 233–241.