Archives of Gynecology and Obstetrics

, Volume 287, Issue 3, pp 541–548

Human papillomavirus early proteins and apoptosis

Gynecologic Oncology

Abstract

Introduction

The human papillomavirus (HPV) associated apoptosis can be primarily attributed to some early proteins, such as E2, E5, E6, E7, and so on. Though these proteins have a low molecular size, they are capable to interact with a series of host cellular regulation proteins to induce or inhibit apoptosis. The oncoproteins E6 can inhibit the apoptosis mainly through p53 pathway. The E5 protein can protect cells from tumor necrosis factor-related apoptosis. The protein E2 protein have regulatory functions in viral transcription and induction of apoptosis. The oncoprotein E7 plays the role in both apoptosis activation and inhibition. In addition, the HPV full-length E2 proteins involve in activating or repressing the transcription of E6/E7, so as to regulating the apoptosis caused by E6 and E7.

Materials and methods

We search major databases (such as Elsevier) with the following selection criteria: HPV, early protein, apoptosis.

Conclusions

In this review, we summary the literature related with E2, E5, E6, and E7 proteins, and describe the regulatory principles and specific mechanism by which HPV early proteins can interfere with apoptosis and trigger gynaecopathias for women.

Keywords

Human papillomavirus Early protein Oncoprotein Apoptosis 

References

  1. 1.
    zur Hausen H (2002) Papillomavirus and cancer: from basic studies to clinical application. Nat Rev Cancer 2:342–350PubMedCrossRefGoogle Scholar
  2. 2.
    de Villiers EM, Fauquet C, Broker TR, Bernard HU, zur Hausen H (2004) Classification of papillomaviruses. Virology 324:17–27PubMedCrossRefGoogle Scholar
  3. 3.
    Kaspersen MD, Larsen PB, Ingerslev HJ, Fedder J, Petersen GB, Bonde J, Hollsberg P (2011) Identification of multiple HPV types on spermatozoa from human sperm donors. PLoS One 6:e18095PubMedCrossRefGoogle Scholar
  4. 4.
    Schlecht NF, Kulaga S, Robitaille J, Ferreira S, Santos M, Miyamura RA, Duarte-Franco E, Rohan TE, Ferenczy A, Villa LL, Franco EL (2001) Persistent human papillomavirus infection as a predictor of cervical intraepithelial neoplasia. JAMA 286:3106–3114PubMedCrossRefGoogle Scholar
  5. 5.
    Alam MS, Ali A, Mehdi SJ, Alyasiri NS, Kazim Z, Batra S, Mandal AK, Rizvi MA (2012) HPV typing and its relation with apoptosis in cervical carcinoma from Indian population. Tumor Biol 33:17–22CrossRefGoogle Scholar
  6. 6.
    Pisani P, Bray F, Parkin DM (2002) Estimates of the world-wild prevalence of cancer for 25 sites in the adult population. Int J Cancer 97:72–81PubMedCrossRefGoogle Scholar
  7. 7.
    zur Hausen H (2009) Papillomaviruses in the causation of human cancers—a brief historical account. Virology 384:260–265PubMedCrossRefGoogle Scholar
  8. 8.
    Gaelle B, Caroline H, Davy VB, Shaira S, Johannes B (2007) Human papillomavirus: E6 and E7 oncogenes. Int J Biochem Cell Biol 39:2006–2011CrossRefGoogle Scholar
  9. 9.
    Longworth MS, Laimins LA (2004) Pathogenesis of human papillomaviruses in differentiating epithelia. Microbiol Mol Biol Rev 68:362–372PubMedCrossRefGoogle Scholar
  10. 10.
    Garnett TO, Duerksen-Hughes PJ (2006) Modulation of apoptosis by human papillomavirus (HPV) oncoproteins. Arch Virol 151:2321–2335PubMedCrossRefGoogle Scholar
  11. 11.
    Mantovani F, Banks L (2001) The human papillomavirus E6 protein and its contribution to malignant progression. Oncogene 20:7874–7887PubMedCrossRefGoogle Scholar
  12. 12.
    Pim D, Banks L (1999) HPV-18 E6* I protein modulates the E6-directed degradation of p53 by binding to full-length HPV-18 E6. Oncogene 18:7403–7408PubMedCrossRefGoogle Scholar
  13. 13.
    Nomine Y, Masson M, Charbonnier S, Zanier K, Ristriani T, Deryckere F, Sibler AP, Desplancq D, Atkinson RA, Weiss E, Orfanoudakis G, Kieffer B, Trave G (2006) Structural and functional annlysis of E6 oncoprotein: insight in the molecular pathways of human papillomavirus-mediated pathogenesis. Mol Cell 21:665–678PubMedCrossRefGoogle Scholar
  14. 14.
    Ristriani T, Nomine Y, Masson M, Weiss E, Trave G (2001) Specific recognition of four way DNA junctions by the C-terminal zinc-binding domain of HPV oncoprotein E6. J Mol Biol 305:729–739PubMedCrossRefGoogle Scholar
  15. 15.
    Huibregtse JM, Scheffner M, Howlwy PM (1991) A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus type 16 or 18. EMBO J 10:4129–4135PubMedGoogle Scholar
  16. 16.
    Scheffner M, Huibregtse JM, Vierstra RD, Howley PM (1993) The HPV-16 E6 and E6AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 75:495–505PubMedCrossRefGoogle Scholar
  17. 17.
    Murray-Zmijewski F, Slee EA, Lu X (2008) A complex barcode underlies the heterogeneous response of p53 to stress. Nat Rev Mol Cell Biol 9:702–712PubMedCrossRefGoogle Scholar
  18. 18.
    Bedard KM, Underbrink MP, Howie HL, Galloway DA (2008) The E6 oncoproteins from human betapalillomavirus differentially activate telomerase through an E6AP-dependent mechanism and prolong the lifepan of primary keratinocytes. J Virol 82:3894–3902PubMedCrossRefGoogle Scholar
  19. 19.
    Watson RA, Thomas M, Banks L, Roberts S (2003) Activity of the human papillomavirus E6 PDZ-binding motif correlates with an enhanced morphological transformation of immortalized human keratinocytes. J Cell Sci 116:4925–4934PubMedCrossRefGoogle Scholar
  20. 20.
    Howie HL, Katzenellenbogen RA, Galloway DA (2009) Papillomavirus E6 proteins. Virology 384:324–334PubMedCrossRefGoogle Scholar
  21. 21.
    Meelis K, Toomas S, Ene U, Mart U (2009) Papillomavirus DNA replication—from initiation to genomic instability. Virology 384:360–368CrossRefGoogle Scholar
  22. 22.
    Blanchette P, Branton PE (2009) Manipulation of the ubiquitin-proteasome pathway by small DNA tumor virus. Virology 384:317–323PubMedCrossRefGoogle Scholar
  23. 23.
    Renata CM, Thais RG, Carlos BN, Maria RB, de Oliveira, Eduardo AD, Maria AG, Goncalves, Edson GS, Carla PK, Ivarne T, Maria AP, Luis R, Christiane PS (2011) Abnormal cell-cycle expression of the proteins p27, mdm2 and cathepsin B in oral squamous-cell carcinoma infected with human papillomavirus. Acta Histochem 113:109–116CrossRefGoogle Scholar
  24. 24.
    Heaton PR, Deyrieux AF, Bian XL, Wilson VG (2011) HPV E6 proteins target Ubc9, the SUMO conjugating enzyme. Virus Res 158:199–208PubMedCrossRefGoogle Scholar
  25. 25.
    Kumar A, Zhao Y, Meng G, Zeng M, Srinivasan S, Delmolino LM, Gao Q, Dimri G, Weber GF, Wazer DE, Band H, Band V (2002) Human papillomovirus oncoprotein E6 inactivates the transcriptional coactivator human ADA3. Mol Cell Biol 22:5801–5812PubMedCrossRefGoogle Scholar
  26. 26.
    Ingrid P, Dana P, Martina D, Michal S (2010) DNA vaccine against human papillomavirus type 16: modification of the E6 oncogene. Vaccine 28:1506–1513CrossRefGoogle Scholar
  27. 27.
    Lee D, Kwon JH, Kim EH, Kim ES, Choi KY (2010) HMGB2 stabilizes p53 by interfering with E6/E6AP-mediated p53 degradation in human papillomavirus-positive HeLa cells. Cancer Lett 1:125–132CrossRefGoogle Scholar
  28. 28.
    Tutik T, Yves N, Cecile L, Etienne W, Gilles T (2002) Protein mutagenesis with mono dispersity-based quality probing: selective inactivation of p53 degradation and DNA-binding properties of HPV E6 oncoprotein. Protein Express Purif 26:357–367CrossRefGoogle Scholar
  29. 29.
    Khoronenkova SV, Dianov GL (2011) The emerging role of Mule and ARF in the regulation of base excision repair. FEBS Lett 585:2831–2835PubMedCrossRefGoogle Scholar
  30. 30.
    Verhelst K, Carpentier I, Beyaert R (2011) Regulation of TNF-induced NF-kB activation by different cytoplasmic ubiquitination events. Cytokine Growth F R 22:277–286CrossRefGoogle Scholar
  31. 31.
    Liu ZG, Zhao LN, Liu YW, Li TT, Fan DM, Chen JJ (2007) Activation of Cdc2 contributes to apoptosis in HPV E6 expressing human keratinocytes in response to therapeutic agents. J Mol Biol 374:334–345PubMedCrossRefGoogle Scholar
  32. 32.
    Yuan CH, Filippova M, Tungteakkhun SS, Duerksen-Hughes PJ, Krstenansky JL (2012) Small molecule inhibitors of the HPV 16-E6 interaction with caspase 8. Bioorg Med Chem Lett (in press)Google Scholar
  33. 33.
    Sima N, Wang SX, Wang W, Kong D, Xu Q, Tian X, Luo A, Zhou JF, Xu G, Meng L, Lu YP, Ma D (2007) Antisense targeting human papillomavirus type 16 E6 and E7 genes contributes to apoptosis and senescence in SiHa cervical carcinoma cells. Gynecol Oncol 106:299–304PubMedCrossRefGoogle Scholar
  34. 34.
    Filippova M, Johnson MM, Bautista M, Filippov V, Fodor N, Tungteakkhum SS, Williams K, Duerksen-Hughes PJ (2007) The large and small isoforms of human papillomavirus type 16 E6 bind to and differentially affect procaspase 8 stability and activity. J Virol 81:4116–4129PubMedCrossRefGoogle Scholar
  35. 35.
    Yael A, Moshe O (2011) P53: guardian of ploidy. Molecul Oncol 5(4):315–323CrossRefGoogle Scholar
  36. 36.
    Contreras-Paredes A, la Cruz-Hernandez ED, Martinez-Ramirez I, Duenas-Gonzalez A, Lizano M (2009) E6 variants of human papillomavirus 18 differentially modulate the protein kinase B/phosphatidylinositol 3 kinase signaling pathway. Virology 383:78–85PubMedCrossRefGoogle Scholar
  37. 37.
    Underbrink MP, Howie HL, Bedard KM, Koop JI, Galloway DA (2008) The E6 proteins from multiple beta HPV types degrade Bak and protect keratinocytes from apoptosis after UVB irradiation. J Virol 82:10408–10417PubMedCrossRefGoogle Scholar
  38. 38.
    Du J, Chen GG, Vlantis AC, Chan PKS, Tsang RKY, van Hasselt CA (2004) Resistance to apoptosis of HPV 16-infected laryngeal cancer cells is associated with decreased Bak and increased Bcl-2 expression. Cancer Lett 205:81–88PubMedCrossRefGoogle Scholar
  39. 39.
    Klingelhutz AJ, Foster SA, Mcdougall JK (1996) Telomerase activation by the E6 gene product of human papillomavirus type 16. Nature 380:79–82PubMedCrossRefGoogle Scholar
  40. 40.
    Gewies A (2003) ApoReview: introduction to apoptosis. http://www.celldeath.de/encyclo/aporev/aporev.htm
  41. 41.
    Garnett TO, Filippova M, Duerksen-Hughes PJ (2006) Accelerated degradation of FADD and procaspase 8 in cells expressing human papilloma virus 16 E6 impairs TRAIL-mediated apoptosis. Cell Death Differ 13:1915–1926PubMedCrossRefGoogle Scholar
  42. 42.
    Borbely AA, Murvai M, Konya J, Beck Z, Gergely L, Li F, Veress G (2006) Effects of human papillomavirus type 16 oncoproteins on surviving gene expression. J Gen Virol 87:287–294PubMedCrossRefGoogle Scholar
  43. 43.
    Gewin L, Galloway DA (2001) E box-dependent activation of telomerase by human papillomavirus type 16 E6 does not require induction of c-Myc. J Virol 75:7198–7201PubMedCrossRefGoogle Scholar
  44. 44.
    Venuti A, Paolini F, Nasir L, Corteggio A, Roperto S, Campo MS, Borzacchiello G (2011) Papillomavirus E5: the smallest oncoprotein with many functions. Mol Cancer 10:140PubMedCrossRefGoogle Scholar
  45. 45.
    Chang JL, Tsao YP, Liu DW, Huang SJ, Lee WH, Chen SL (2001) The expression of HPV-16 E5 protein in squamous neoplastic changes in the uterine cervix. J Biomed Sci 8:206–213PubMedCrossRefGoogle Scholar
  46. 46.
    Conrad M, Bubb VJ, Schlegel R (1993) The human papillomavirus type 6 and 16 E5 proteins are membrane-associated proteins which associated with the 16-kilodalton pore-forming protein. J Virol 67:6170–6178PubMedGoogle Scholar
  47. 47.
    Borzacchiello G, Roperto F, Campo MS, Venuti A (2010) 1st international workshop on papillomavirus E5 oncogene—a report. Virology 408:135–137PubMedCrossRefGoogle Scholar
  48. 48.
    Chen S, Mounts P (1990) Transforming activity of E5a protein of human papillomavirus type 6 in HIH 3T3 and C127 cells. J Virol 64:3226–3233PubMedGoogle Scholar
  49. 49.
    Hu LL, Potapova TA, Li SB, Rankin S, Gorbsky GJ, Angeletti PC, Ceresa BP (2010) Expression of HPV 16 E5 produces enlarged nuclei and polyploidy through endoreplication. Virology 405:342–351PubMedCrossRefGoogle Scholar
  50. 50.
    Kabsch K, Alonso A (2002) The human papillomavirus type 16 E5 protein impairs TRAIL- and FasL-mediated apoptosis in HaCaT cells by different mechanisms. J Virol 76:12162–12172PubMedCrossRefGoogle Scholar
  51. 51.
    Kabsch K, Mossadegh N, Kohl A, Komposch G, Schenkel J, Alonso A, Tomakidi P (2004) The HPV-16 E5 protein inhibits TRAIL- and FasL-mediated apoptosis in human keratinocyte reft cultures. Intervirology 47:48–56PubMedCrossRefGoogle Scholar
  52. 52.
    Zhang BY, Li P, Wang E, Brahmi Z, Dunn KW, Blum JS, Roman A (2003) The E5 protein of human papillomavirus type 16 perburbs MHC class II antigen maturation in human foreskin keratinocytes treated with interferon-γ. Virology 310:100–108PubMedCrossRefGoogle Scholar
  53. 53.
    Wang X, Shi Q, Xu K, Gao C, Chen C, Li XL, Wang GR, Tian C, Han J, Dong XP (2011) Familial CJD associated PrP mutants within transmembrane region induced Ctm-PrP retention in ER and trigger apoptosis by ER stress in SH-SY5Y cells. PLoS One 6:e14602PubMedCrossRefGoogle Scholar
  54. 54.
    Xu K, Wang X, Shi Q, Chen C, Tian C, Li XL, Zhou RM, Chu YL, Dong XP (2010) Human prion protein mutants with deleted and inserted octarepeats undergo different pathways to trigger cell apoptosis. J Mol Neurosci 43:225–234PubMedCrossRefGoogle Scholar
  55. 55.
    Sudarshan SR, Schlegel R, Liu XF (2010) The HPV-16 E5 protein represses expression of stress pathway genes XBP-1 and COX-2 in genital keratinocytes. Biochem Biophys Res Co 399:617–622CrossRefGoogle Scholar
  56. 56.
    Condjella R, Liu X, Suprynowicz F, Yuan H, Sudarshan S, Dai Y, Schlegel R (2009) The canine papillomavirus E5 protein signals from the endoplasmic reticulum. J Virol 83:12833–12841PubMedCrossRefGoogle Scholar
  57. 57.
    Schiffman M, Castle PE (2005) The promise of global cervical-cancer prevention. N Engl J Med 353:2101–2104PubMedCrossRefGoogle Scholar
  58. 58.
    Kim SH, Oh JM, No JH, Bang YJ, Juhnn YS, Song YS (2009) Involvement of NFkappaB and AP-1 in COX-2 upregulation by human papillomavirus 16 E5 oncoprotein. Carcinogenesis 30:753–757PubMedCrossRefGoogle Scholar
  59. 59.
    Woodworth CD, Diefendorf LP, Jette DF, Mohammed A, Moses MA, Searleman SA, Stevens DA, Wilton KM, Mondal S (2011) Inhibition of the epidermal growth factor receptor by erlotinib prevents immortalization of human cervical cells by human papillomavirus type 16. Virology 421:19–27PubMedCrossRefGoogle Scholar
  60. 60.
    Oh JM, Lee YI, Song YS, Kim WH, Juhnn YS (2009) Human papillomavirus E5 protein induces expression of the EP4 subtype of prostaglandin E2 receptor in cyclic AMP response element-dependent pathways in cervical cancer cells. Carcinogenesis 30:141–149PubMedCrossRefGoogle Scholar
  61. 61.
    Wells SI, Francis DA, Karpova AY, Dowhanick JJ, Benson JD, Howley PM (2000) Papillomavirus E2 induces senescence in HPV-positive cells via pRB and p21-dependent pathway. EMBO J 19:5762–5771PubMedCrossRefGoogle Scholar
  62. 62.
    Brown C, Kowalczyk AM, Taylor ER, Morgan IM, Gaston K (2008) p53 represses human papillomavirus type 16 DNA replication via the viral E2 protein. Virol J 5:5PubMedCrossRefGoogle Scholar
  63. 63.
    Bernudez-Morales VH, Peralta-Zaragoza O, Guzman-Olea E, Garcia-Carranca A, Bahena-Roman M, Alcocer-Gonzalez JM, Madrid-Marina V (2009) HPV 16 E2 protein induces apoptosis in human and murine HPV 16 transformed epithelial cells and has antitumoral effects in vivo. Tumor Biol 30:61–72CrossRefGoogle Scholar
  64. 64.
    Thierry F, Demeret C (2008) Direct activation of caspase 8 by the proapoptotic E2 protein of HPV 18 independent of adaptor proteins. Cell Death Differ 15:1356–1363PubMedCrossRefGoogle Scholar
  65. 65.
    Parish JL, Kowalczyk A, Chen HT, Roeder GE, Sessions R, Buckle M, Gaston K (2006) E2 proteins from high- and low-risk human papillomavirus types differ in their ability to bind p53 and induce apoptotic cell death. J Virol 80:4580–4590PubMedCrossRefGoogle Scholar
  66. 66.
    Lagunas-Martinez A, Madrid-Marina V, Gariglio P (2010) Modulation of apoptosis by early human papillomavirus proteins in cervical cancer. BBA-Rev Cancer 1805:6–16Google Scholar
  67. 67.
    McLaughlin-Drubin ME, Munger K (2009) The human papillomavirus E7 oncoprotein. Virology 384:335–344PubMedCrossRefGoogle Scholar
  68. 68.
    Toscano-Garibay JD, Benitez-Hess ML, Alvarez-Salas LM (2011) Isolation and characterization of an RNA aptamer of the HPV-16 E7 oncoprotein. Arch Med Res 42:88–96PubMedCrossRefGoogle Scholar
  69. 69.
    Ohlenschlager O, Seiboth T, Zengerling H, Briese L, Marchanka A, Ramachandran R, Baum M, Korbas M, Meyer-Klaucke W, Durst M, Gorlach M (2006) Solution structure of the partially folded high-risk human papillomavirus 45 oncoprotein E7. Oncogene 25:5953–5959PubMedCrossRefGoogle Scholar
  70. 70.
    Liu X, Clements A, Zhao K, Marmorstein R (2006) Structure of human Papillomavirus E7 oncoprotein and its mechanism for inactivation of the retinoblastoma tumor suppressor. J Biol Chem 281:578–586PubMedCrossRefGoogle Scholar
  71. 71.
    Ghim S, Jenson AB, Bubier JA, Silva KA, Smith RS, Sundberg JP (2008) Cataracts in transgenic mice caused by a human papillomavirus type 18 E7 oncogene driven by KRT1-14. Exp Mol Pathol 85:77–82PubMedCrossRefGoogle Scholar
  72. 72.
    Zimmermann M, Koreck A, Meyer N, Basinski T, Meiler F, Simone B, Woehrl S, Moritz K, Eiwegger T, Schmid-Grendelmeier P, Kemeny L, Akdis CA (2011) TNF-like weak inducer of apoptosis and TNF-alpha cooperate in the induction of keratinocyte apoptosis. J Allergy Clin Immun 127:200–207PubMedCrossRefGoogle Scholar
  73. 73.
    Pardali K, Moustakas A (2007) Actions of TGF-β as tumor suppressor and pro-metastatic factor in human cancer. BBA-Rev Cancer 1775:21–62Google Scholar
  74. 74.
    DeMasi J, Huh KW, Nakatani Y, Munger K, Howley PM (2005) Bovine papillomavirus E7 transformation function correlates with cellular p600 protein binding. Proc Natl Acad Sci USA 102:11486–11491PubMedCrossRefGoogle Scholar
  75. 75.
    DeMasi J, Chao MC, Kumar AS, Howley PM (2007) Bovine papillomavirus E7 oncoprotein inhibits anoikis. J Virol 81:9419–9425PubMedCrossRefGoogle Scholar
  76. 76.
    Severino A, Abbruzzese C, Manente L, Valderas AA, Mattarocci S, Federico A, Starace G, Chersi A, Mileo AM, Paggi MG (2007) Human papillomavirus-16 E7 interacts with Siva-2 and modulates apoptosis in HaCaT human immortalized keratinocytes. J Cell Physiol 212:118–125PubMedCrossRefGoogle Scholar
  77. 77.
    Doorbar J (2006) Molecular biology of human papillomavirus infection and cervical cancer. Clin Sci (Lond) 110:525–541CrossRefGoogle Scholar
  78. 78.
    Mazumder D, Singh RK, Mitra S, Dutta S, Chakraborty C, Basu PS, Mondal RK, Roychoudhury S, Panda CK (2011) Genetic and epigenetic changes of HPV 16 in cervical cancer differentially regulate E6/E7 expression and associate with disease progression. Gynecol Oncol 123:597–604CrossRefGoogle Scholar
  79. 79.
    Tang S, Tao M, McCoyJr JP, Zheng ZM (2006) The E7 oncoprotein is translated from spliced E6I transcripts in high-risk human papillomavirus type 16-or type 18-positive cervical cancer cell lines via translation reinitiation. J Virol 80:4249–4263PubMedCrossRefGoogle Scholar
  80. 80.
    Dell G, Gaston K (2001) Human papillomavirus and their role in cervical. Cell Mol Life Sci 58:1923–1942PubMedCrossRefGoogle Scholar
  81. 81.
    Wu X, Levine AJ (1994) p53 and E2F1 cooperate to mediate apoptosis. Proc Natl Acad Sci 91:3602–3606PubMedCrossRefGoogle Scholar
  82. 82.
    Frattini MG, Hurst SD, Lim HB, Swaminathan S, Laimins LA (1997) Abrogation of a mitotic checkpoint by E2 proteins from oncogenic human papillomaviruses correlates with increased turnover of the p53 tumor suppressor protein. EMBO J 16:318–331PubMedCrossRefGoogle Scholar
  83. 83.
    Bouvard V, Storey A, Pim D, Banks L (1994) Characterization of the human papillomavirus E2 protein: evidence of trans-activation and trans-repression in cervical keratinocytes. EMBO J 13:5451–5459PubMedGoogle Scholar
  84. 84.
    Kim K, Gamer-Hamrick PA, Fisher C, Lee D, Lambert PF (2003) Methylation patterns of papillomavirus DNA, its influence on E2 function, and implications in viral infection. J Virol 77:12450–12459PubMedCrossRefGoogle Scholar
  85. 85.
    Dong XP, Stubenrauch F, Beyer-Finkler E, Pfister H (1994) Prevalence of deletions of YY1-binding sites in episomal HPV 16 DNA from cervical cancers. Int J Cancer 58:803–808PubMedCrossRefGoogle Scholar
  86. 86.
    Pett M, Coleman N (2007) Integration of high-risk human papillomavirus: a key event in cervical carcinogenesis? J Pathol 212:356–367PubMedCrossRefGoogle Scholar
  87. 87.
    Arisa-Pulido H, Peyton CL, Joste NE, Vargas H (2006) Wheeler C.M. Human papillomavirus type 16 integration in cervical carcinoma in situ and in invasive cervical cancer. J Clin Microbiol 44:1755–1762CrossRefGoogle Scholar
  88. 88.
    Bhattacharjee B, Sengupta S (2006) CpG methylation of HPV 16 LCR at E2 binding site proximal to P97 is associated with cervical cancer in presence of intact E2. Virology 354:280–285PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Department of Obstetrics and GynecologyFirst People’s Hospital of Yunnan ProvinceKunmingPeople’s Republic of China
  2. 2.Kunhua Affiliated Hospital of KunmingUniversity of Science and TechnologyKunmingPeople’s Republic of China
  3. 3.Department of RadiologyFirst People’s Hospital of Yunnan ProvinceKunmingPeople’s Republic of China

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