Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
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ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
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Advances in Clinical and Experimental Medicine

2012, vol. 21, nr 2, March-April, p. 235–244

Publication type: review article

Language: English

The Role of Human Papillomavirus in the Malignant Transformation of Cervix Epithelial Cells and the Importance of Vaccination Against This Virus

Rola HPV w mechanizmie transformacji nowotworowej komórek nabłonka szyjki macicy oraz znaczenie szczepionki przeciwko temu wirusowi

Urszula Ciesielska1,, Katarzyna Nowińska1,, Marzena Podhorska-Okołów1,, Piotr Dzięgiel1,

1 Department of Histology and Embryology, Wroclaw Medical University


Human papillomavirus (HPV) belongs to the diverse group of sexually transmitted viruses that manifest affinity to the squamous epithelia of the skin and mucous membranes. Over 100 types of HPV have been described and identified in human tissues, and it has been proved that persistent infection with high-risk types of the virus (types 16 and 18 in particular) could lead to cervical cancer. High-risk HPV types have been found in approximately 70% of all cases of cervical cancer worldwide. The aim of this study was to describe the role of HPV in the process of neoplastic transformation in epithelial cells and to emphasize the prophylactic significance of vaccinations against the virus.


Wirus brodawczaka ludzkiego (HPV – human papillomavirus) jest zaliczany do zróżnicowanej grupy wirusów przenoszonych drogą płciową, wykazujących powinowactwo do nabłonka wielowarstwowego płaskiego skóry oraz błon śluzowych człowieka. Do chwili obecnej wyodrębniono ponad 100 typów tego wirusa i udowodniono, iż przetrwałe zakażenie jego onkogennymi typami (zwłaszcza 16 i 18) może prowadzić do rozwoju raka szyjki macicy. Obecność tych typów HPV stwierdzono w około 70% przypadków raka szyjki macicy na świecie. Celem pracy było omówienie roli HPV w procesie transformacji nowotworowej komórek nabłonkowych oraz podkreślenie znaczenia profilaktycznego zastosowania szczepionki przeciw temu wirusowi.

Key words

human papillomavirus (HPV), neoplastic transformation, cancer of uterine cervix, vaccine against HPV

Słowa kluczowe

wirus brodawczaka ludzkiego (HPV), transformacja nowotworowa, rak szyjki macicy, szczepionka przeciw HPV

References (64)

  1. Gross G: HPV-vaccination against cervical carcinoma: will it really work? Med Microbiol Immunol 2007, 196, 121–125.
  2. Naucler P, Ryd W, Törnberg S, Strand A, Wadell G, Elfgren K, Rådberg T, Strander B, Forslund O, Hansson BG, Hagmar B, Johansson B, Rylander E, Dillner J: Efficacy of HPV DNA testing with cytology triage and/or repeat HPV DNA testing in primary cervical cancer screening. J Cancer Inst 2009, 101, 88–99.
  3. Schmitt M, Pawlita M: The HPV transcriptome in HPV 16 positive cell lines. Mol Cell Probes 2011, 25, 108–113.
  4. Beaudenon S, Huibregtse J M: HPV E6, E6AP and cervical cancer. BMC Biochemistry 2008, 9, 1, 4.
  5. Morshed K: Udział wirusa brodawczaka ludzkiego (HPV) w etiopatogenezie nowotworów głowy i szyi. Otolaryngologia 2004, 3, 3, 91–96.
  6. Sotlar K, Diemer D, Dethleffs A, Hack Y, Stubner A, Vollmer N, Menton S, Menton M, Dietz K, Wallwiener D, Kandolf R, Bültmann B: Detection and typing human Papillmavirus by E6 nested multiplex PCR. J Clin Microbiol 2004, 42, 7, 3176–3184.
  7. Narisawa-Saito M, Kiyono T: Basic mechanisms of high-risk human papillomavirus-induced carcinogenesis: roles of E6 and E7 proteins. Cancer Sci 2007, 98, 10, 1505–1911.
  8. Adam E Berkova, Daxnerova Z, Icenogle J, Reeves WC, Kaufman RH: Papillomavirus detection: demographic and behavioral characteristics influencing the identification of cervical disease. Am J Obstet Gynecol 2000, 182, 257–264
  9. zur Hausen H: Papillomavirus causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst 2000, 92, 9, 690–698.
  10. Jenkins D: A review of cross-protection against oncogenic HPV by an HPV-16/18 ASO4-adjuvanted cervical cancer vaccine: Importance of virological and clinical endpoints and implications for mass vaccination in cervical cancer prevention. Gynecol Oncol 2008, 110, 18–25.
  11. Scheffner M, Whitaker NJ: Human papillomavirus-induced carcinogenesis and the ubiquitin-proteasome system. Semin Cancer Biol 2003, 13, 1, 59–67.
  12. Tang S, Tao M, McCoy JP Jr, Zheng ZM: The E7 oncoprotein is translated from spliced E6*I transcripts in highrisk human papillomavirus type 16- or type 18-positive cervical cancer cell lines via translation reinitiation. J Virol 2006, 80, 9, 4249–4263.
  13. Villanueva R, Morales-Peza N, Castelán-Sánchez I, García-Villa E, Tapia R, Cid-Arregui A, García-Carrancá A, López-Bayghen E, Gariglio P: Heparin (GAG-hed) inhibits LCR activity of human papillomavirus type 18 by decreasing AP1 binding. BMC Cancer 2006, 6, 218.
  14. Mistry N, Simonsson M, Evander M: Transcriptional activation of the human papillomavirus type 5 and 16 long control region in cells from cutaneous and mucosal origin. Virol J 2007, 12, 4, 27.
  15. Keam SJ, Harper DM: Human papillomavirus types 16 and 18 vaccine (recombinant, AS04 adjuvanted, adsorbed) [Cervarix]. Drugs 2008, 68, 3, 359–372.
  16. Kędzia W, Pruski D, Józefiak A, Rokita W, Spaczyński M: Genotyping of oncogenic human papilloma viruses in women with HG SIL diagnosis. Ginekol Pol 2010, 81, 740–744.
  17. Schmeink CE, Melchers WJG, Siebers AG, Quint WGV, Massuger LFAG, Bekkers RLM: Human Papillomavirus Persistence in Young Unscreened Women, a Prospective Cohort Study. PLoS One 2011, 6, 11, e27937.
  18. Chieng DC, Gallaspy S, Yang H, Roberson J, Eltoum I: Women with atypical glandular cells: a long-term followup study in a high-risk population. Am J Clin Pathol 2004, 122, 4, 575–579.
  19. Lowy DR, Solomon D, Hildesheim A, Schiller JT, Schiffman M: Human papillomavirus infection and the primary and secondary prevention of cervical cancer. Cancer 2008, 1, 113, 7, 1980–1993.
  20. Yang X, Jin G, Nakao Y, Rahimtula M, Pater MM, Pater A: Malignant transformation of HPV-16 immortalized human endocervical cells by cigarette smoke condensate and characterization of multistage carcinogenesis. Int J Cancer 1996, 65, 338–344.
  21. Appleby P, Beral V, Berrington de González A, Colin D, Franceschi S, Goodill A, Green J, Peto J, Plummer M, Sweetland S: Carcinoma of the cervix and tobacco smoking: collaborative reanalysis of individual data on 13,541 women with carcinoma of the cervix and 23,017 women without carcinoma of the cervix from 23 epidemiological studies.
  22. Tarka A, Szczepańska M, Raczyńska D, Pruski D, Kędzia W, Opala T: Risk factors and frequency of occurrence of HPV DNA of high oncogenic types in paraepidermal epithelium cells of the uterine cervix, in the trophoblast, and in the peripheral blood of pregnant patients. Ginekol Pol 2008, 79, 871–876.
  23. Tarka A, Szczepańska M, Rokita W, Józefiak A, Kędzia W: Risk assessment of chronic HPV HR infection in babies who contacted the virus in the perinatal period. Ginekol Pol 2011, 82, 664–669.
  24. Saslow D, Castle PE, Cox JT, Davey DD, Einstein MH, Ferris DG, Goldie SJ, Harper DM, Kinney W, Moscicki AB, Noller KL, Wheeler CM, Ades T, Andrews KS, Doroshenk MK, Kahn KG, Schmidt C, Shafey O, Smith RA, Partridge EE, Gynecologic Cancer Advisory Group, Garcia F: American Cancer Society Guideline for human Papillomavirus (HPV) Vaccine Use to Prevent Cervical Cancer and Its Precursors. CA Cancer J Clin 2007, 57, 7–28.
  25. Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S: Human papillomavirus and cervical cancer. Lancet 2007, 8, 370, 9590, 890–907.
  26. Olejnik A, Waksmański B, Korona K, Drębkowski A: Human papilloma virus infection of the uterine cervix in pathological condition in aspect of preventive vaccination. Ann Acad Med Siles 2007, 61, 3.
  27. Petersen I, Schewe C, Schlüns K, Dietel M, Speich N, Schmitt C, Bollmann M, Sotlar K, Bültmann B, DoursZimmermann MT, Padberg B, Zimmermann DR: Inter-laboratory validation of PCR-based HPV detection in pathology specimens. Virchows Arch 2007, 451, 3, 701–716.
  28. Pett M, Coleman N: Integration of high-risk human papillomaviruses: a key event in cervical carcinogenesis? J Pathol 2007, 212, 4, 356–367.
  29. Ling X, Shixuan W, Changyu W, Qian X, Pengcheg L, Xun T, Peng W, Wei W, Dongrui D, Jianfeng Z, Ding M: The pro-angiogenic factor stimulated by human papillomavirus type 16 E6 and E7 protein in C33A and human fibroblasts. Oncol Rep 2009, 21, 25–31.
  30. zur Hausen H: Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2002, 2, 342–350.
  31. Winters U, Roden R, Kitchener H, Stern P: Progress in the development of a cervical cancer vaccine. Ther Clin Risk Manag 2006, 2, 3, 259–269.
  32. Majewski S: Vaccine against human papilloma viruses (HPV) (in Polish). Alergia 2002, 3, 14.
  33. Munger K, Yee CL, Phelps WC, Pietenpol JA, Moses HL, Holewy PM: Biological activities molecular targets of the human papillomavirus E7 onkoprotein. Oncogene 2001, 20, 7888–7898.
  34. Hengstermann A, Linares LK, Ciechanover A, Whitaker NJ, Scheffner M: Complete switch from Mdm2 to human papillomavirus E6-mediated degradation of p53 in cervical cancer cells. Proc Natl Acad Sci 2001, 98, 1218–1223.
  35. Ganguly N, Parihar SP: Human papillomavirus E6 and E7 oncoproteins as risk factors for tumorigenesis. J Biosci 2009, 34, 113–123.
  36. Bernard X, Robinson P, Nominé Y, Masson M, Charbonnier S, Ramirez-Ramos JR, Deryckere F, Travé G, Orfanoudakis G: Proteosomal Degradation of p53 by Human Papillmavirus E6 Oncoprotein Relies on the Structural Integrity of p53 Core Domain. Plos One 2011, 6, 10, e25981.
  37. Tomaic V, Pim D, Thomas M, Massimi P, Myers MP, Banks L: Regulation of the human papillomavirus type 18 E6/E6AP ubiquitin ligase complex by the HECT domain-containing protein EDD. J Virol 2011, 85, 7, 3120– 3127.
  38. Mantovani F, Banks L: The Human Papillomavirus E6 protein and its contribution to malignant progression. Oncogene 2001, 20, 7874–7887.
  39. Garnett T, Filippova M, Duerksen-Hughes PJ: Accelerated degradation of FADD and procaspase 8 in cells expressing human papilloma virus 16 E6 impairs TRAIL-mediated apoptosis. Cell Death Differ 2006, 13, 1915– 1926.
  40. James MA, Lee JH, Klingelhutz AJ: Human papillomavirus type 16 E6 activates NF-B, induces cIAP-2 expression, and protects against apoptosis in a PDZ binding motif-dependent manner. J Virol 2006, 80, 5301–5307.
  41. Pendino F, Tarkanyi I, Dudognon C, Hillion J, Lanotte M, Aradi J, Segal-Bandirdjian E: Telomeres and telomerase; Pharmacological targets for new anticancer strategies? Curr Cancer Drug Targets 2006, 6, 147–180.
  42. Gewin L, Myers H, Kiyono T, Galloway DA: Identification of a novel telomerase repressor that interacts with the human papillomavirus type 16 E6/E6-AP complex. Genes Dev 2004, 18, 2269–2282.
  43. Huang SM, McCance DJ: Down regulation of the interleukin-8 promoter by human papillomavirus type 16 E6 and E7 through effects on CREB binding protein/p300 and P/CAF. J Virol 2002, 76, 17, 8710–8721.
  44. Kumar A, Zhao Y, Meng G, Zeng M, Srinivasan S, Delmolino LM, Gao Q, Dimri G, Weber GF, Wazer DE, Band H, Band V: Human papillomavirus oncoprotein E6 inactivates the transcriptional coactivator human ADA3. Mol Cell Biol. 2002, 22, 5801–5812.
  45. Syrjänen SM, Syrjänen KJ: New concepts on the role of human papillomavirus in cell cycle regulation. Ann Med 1999, 31, 175–187.
  46. Longworth MS, Laimins LA: The binding of histone deacetylases and the integrity of zinc finger-like motifs of the E7 protein are essential for the life cycle of human papillomavirus type 31. J Virol 2004, 78, 3533–3541.
  47. Arroyo M, Bagchi S, Raychaudhuri P: Association of the human papillomavirus type 16 E7 protein with the S-phase-specific E2F-cyclin A complex. Mol Cell Biol 1993, 13, 6537–6546.
  48. Zerfass K, Schulze A, Spitkovsky D, Friedman V, Henglein B, Jansen-Dürr P: Sequential activation of cyclin E and cyclin A gene expression by human papillomavirus type 16 E7 through sequences necessary for transformation. J Virol 1995, 69, 6389–6399.
  49. Zerfass-Thome K, Zwerschke W, Mannhardt B, Tindle R, Botz JW, Jansen-Dürr P: Inactivation of the cdk inhibitor p27KIP1 by the human papillomavirus type 16 E7 oncoprotein. Oncogene 1996, 13, 2323–2330.
  50. Funk JO, Waga S, Harry JB, Espling E, Stillman B, Galloway DA: Inhibition of CDK activity and PCNAdependent DNA replication by p21 is blocked by interaction with the HPV-16 E7 oncoprotein. Genes Dev 1997, 11, 2090–2100.
  51. Cheng YW, Lee H, Shiau MY, Wu TC, Huang TT, Chang YH: Human papillomavirus type 16/18 up-regulates the expression of interleukin-6 and antiapoptotic Mcl-1 in non-small cell lung cancer. Clin Cancer Res 2008, 14, 4705–4712.
  52. Barnard P, McMillan NA: The human papillomavirus E7 oncoprotein abrogates signaling mediated by interferonalpha. Virology 1999, 259, 305–313.
  53. Um SJ, Rhyu JW, Kim EJ, Jeon KC, Hwang ES, Park JS: Abrogation of IRF-1 response by high-risk HPV E7 protein in vivo. Cancer Lett 2002, 179, 205–212.
  54. Buck CB, Cheng N, Thompson CD, Lowy DR, Steven AC, Schiller JT, Trus BL: Arrangement of L2 within the papillomavirus capsid. J Virol 2008, 82(11), 5190–5197.
  55. Kędzia W, Józefiak A, Pruski D, Rokita W, Spaczyński M: Human papilloma virus genotyping in women with CIN 1. Ginekol Pol 2010, 8, 664–667.
  56. Stern PL: Immune control of human papillomavirus (HPV) associated anogenital disease and potential for vaccination. J Clin Virol 2005, 32, 1, 72–81.
  57. Villa LL: Overview of the clinical development and results of a quadrivalent HPV (types 6, 11, 16, 18) vaccine. Int J Infect Dis 2007, 11, 2, 17–25.
  58. Stanley M: Immunobiology of HPV and HPV vaccines. Gynecol Oncol 2008, 109, 2, 15–21.
  59. Markowitz LE, Dunne E F, Saraiya M, Lawson HW, Chesson H, Unger ER: Quadrivalent Human Papillomavirus Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2007, 23, 56, 1–24.
  60. Yeager MD, Aste-Amezaga M, Brown DR, Martin MM, Shah MJ, Cook JC, Christensen ND, Ackerson C, Lowe RS, Smith JF, Keller P, Jansen KU: Neutralization of human papillomavirus (HPV) pseudovirions: a novel and efficient approach to detect and characterize HPV neutralizing antibodies. Virology 2000, 78, 2, 570–577.
  61. Spaczyński M, Kędzia W: HPV viruses and carcinoma of uterine cervix. Vaccinations against HPV. Prophylaxis against uterine cervix carcinoma and agaionst other lesions linked to HPV infecton (in Polish), Majewski S, Sikorski M, Wydawnictwo Czelej 2007, Ist edition, 53–69.
  62. The FUTURE II Study Group: Quadrivalent vaccine against Human Papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007, 10, 1915–1927.
  63. Joura EA, Leodolter S, Hernandez-Avila M, Wheeler CM, Perez G, Koutsky LA, Garland SM, Harper DM, Tang GW, Ferris DG, Steben M, Jones RW, Bryan J, Taddeo FJ, Bautista OM, Esser MT, Sings HL, Nelson M, Boslego JW, Sattler C, Barr E, Paavonen J: Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like-particle vaccine against high-grade vulval and vaginal lesions: a combined analysis of three randomised clinical trials. Lancet 2007, 19, 369, 9574, 1693–1
  64. Kotarski J, Basta A, Dębski R, Karowicz-Bilińska A, Kędzia W, Niemiec T, Nowak-Markwitz E, Olejek A, Poręba R, Spaczyński M, Wysocki J, Polish Gynaecologic Society: The statement of Polish Gynecological Society experts about human papillomavirus (HPV) vaccine use to prevent cervical cancer. Ginekol Pol 2009, 80, 11, 870–876.