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Functional implication of sequence variation in the long control region and E2 gene among human papillomavirus type 18 variants

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Abstract

Cervical cancer incidence remains highly frequent in developing countries. It is possible that populations of these countries are exposed to more oncogenic human papillomavirus (HPV) variants. Functional differences among high-risk HPV variants have been described, suggesting repercussions on their oncogenic potential. In this report, we demonstrate that the long control region (LCR) of HPV18 variants has distinct transcriptional activities in different cervical cancer cell lines. African (Af)-LCR possessed the lowest transcriptional activity; its sequence harbors the highest number of nucleotide changes among the HPV18 variants analyzed. Some of these embedded in identified transcription-factor-binding sites, suggesting a less aggressive biological activity possibly involved in a slower progression of cervical lesions. Asian-Amerindian LCR showed distinct activities among cell types, while European LCR activity was similar in cell lines tested. Despite multiple nucleotide substitutions found in HPV18 E2 variant genes, their repressive activities over homologous LCRs were not distinct among variants.

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References

  1. Muñoz N (2000) Human papillomavirus and cancer: the epidemiological evidence. J Clin Virol 19:1–5

    Article  PubMed  Google Scholar 

  2. Calleja-Macias IE, Kalantari M, Huh J, Ortiz-Lopez R, Rojas-Martinez A, Gonzalez-Guerrero JF, Williamson AL, Hagmar B, Wiley DJ et al (2004) Genomic diversity of human papillomavirus-16, 18, 31, and 35 isolates in a Mexican population and relationship to European, African, and Native American variants. Virology 319:315–323

    Article  PubMed  CAS  Google Scholar 

  3. Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM (1990) The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63:1129–1136

    Article  PubMed  CAS  Google Scholar 

  4. zur Hausen H (1994) Molecular pathogenesis of cancer of the cervix and its causation by specific human papillomavirus types. Curr Top Microbiol Immunol 186:131–156

    PubMed  CAS  Google Scholar 

  5. Butz K, Hoppe-Seyler F (1993) Transcriptional control of human papillomavirus oncogene expression: composition of HPV type 18 upstream regulatory region. J Virol 67:6476–6486

    PubMed  CAS  Google Scholar 

  6. Stünkel W, Bernard HU (1999) The chromatin structure of the long control region of human papillomavirus type 16 represses viral oncoprotein expression. J Virol 73:1918–1930

    PubMed  Google Scholar 

  7. Badal S, Badal V, Calleja-Macias IE, Kalantari M, Chuang LS, Li BF, Bernard HU (2004) The human papillomavirus 18 genome is efficiently targeted by cellular DNA methylation. Virology 324:483–492

    Article  PubMed  CAS  Google Scholar 

  8. Tan SH, Leong LEC, Walker PA, Bernard HU (1994) The human papillomavirus type 16 E2 transcription factor binds with low cooperativity to two flanking sites and represses the E6 promoter through displacement of Sp1 and TFIID. J Virol 68:6411–6420

    PubMed  CAS  Google Scholar 

  9. Thierry F, Howley PM (1991) Functional analysis of E2-mediated repression of the HPV 18 P105 promoter. New Biol 3:90–100

    PubMed  CAS  Google Scholar 

  10. Dowhanick JJ, McBride AA, Howley PM (1995) Suppression of cellular proliferation by the papillomavirus E2 protein. J Virol 69:7791–7799

    PubMed  CAS  Google Scholar 

  11. Desaintes C, Demeret C, Goyat S, Yaniv M, Thierry F (1997) Expression of the papillomavirus E2 protein in HeLa cells leads to apoptosis. EMBO J 16:504–514

    Article  PubMed  CAS  Google Scholar 

  12. Burger RA, Monk BJ, Kurosaki T, Anton-Culver H, Vasilev SA, Berman ML, Wilczynski SP (1996) Human papillomavirus type 18: association with poor prognosis in early stage cervical cancer. J Natl Cancer Inst 88:1361–1368

    Article  PubMed  CAS  Google Scholar 

  13. Bulk S, Berkhof J, Bulkmans NW, Zielinski GD, Rozendaal L, Van Kemenade FJ, Snidjers PJ, Meijer CJ (2006) Preferential risk of HPV16 for squamous cell carcinoma and of HPV18 for adenocarcinoma of the cervix compared to woman with normal cytology in The Netherlands. Br J Cancer 94:171–175

    Article  PubMed  CAS  Google Scholar 

  14. Burk RD, Terai M, Gravitt PE, Briton LA, Kurman RJ, Barnes WA, Greenberg MD, Hadjimichael OC, Fu L et al (2003) Distribution of human papillomavirus types 16 and 18 variants in squamous cell carcinomas and adenocarcinomas of the cervix. Cancer Res 63:7215–7220

    PubMed  CAS  Google Scholar 

  15. Lizano M, Berumen J, Guido MC, Casas L, Garcia-Carranca A (1997) Association between human papillomavirus type 18 variants and histopathology of cervical cancer. J Natl Cancer Inst 89:1227–1231

    Article  PubMed  CAS  Google Scholar 

  16. McLachlin CM, Tate JE, Zitz JC, Sheets EE, Crum CP (1994) Human papillomavirus type 18 and intraepithelial lesions of the cervix. Am J Pathol 144:141–147

    PubMed  CAS  Google Scholar 

  17. Ong CK, Chan SY, Campo MS, Fujinaga K, Mavromara-Nazos P, Labropoulou V, Pfister H, Tay SK, ter Meulen J et al (1993) Evolution of human papillomavirus type 18: an ancient phylogenetic root in Africa and intratype diversity reflect coevolution with human ethnic groups. J Virol 67:6424–6431

    PubMed  CAS  Google Scholar 

  18. Chen Z, DeSalle R, Schiffman M, Herrero R, Burk R (2009) Evolutionary dynamics of variant genomes of human papillomavirus types 18, 45, and 97. J Virol 83:1443–1445

    Article  PubMed  CAS  Google Scholar 

  19. Da Costa MM, Hogeboom CJ, Holly EA, Palefsky JM (2002) Increased risk of high-grade anal neoplasia associated with a human papillomavirus type 16 E6 sequence variant. J Infect Dis 185:1229–1237

    Article  PubMed  CAS  Google Scholar 

  20. Giannoudis A, Duin M, Snijders PJ, Herrington CS (2001) Variation in the E2-binding domain of HPV-16 is associated with high-grade squamous intraepithelial lesions of the cervix. Br J Cancer 84:1058–1063

    Article  PubMed  CAS  Google Scholar 

  21. Kammer C, Warthorst U, Torrez-Martinez N, Wheeler CM, Pfister H (2000) Sequence analysis of the long control region of human papillomavirus type 16 variants and functional consequences for P97 promoter activity. J Gen Virol 81:1975–1981

    PubMed  CAS  Google Scholar 

  22. Veress G, Murvai M, Szarka K, Juhász A, Kónya J, Gergely L (2001) Transcriptional activity of human papillomavirus type 16 variants having deletions in the long control region. E J Cancer 37:1946–1952

    Article  CAS  Google Scholar 

  23. Sichero L, Franco E, Villa LL (2005) Different P105 promoter activities among natural variants of human papillomavirus type 18. J Infect Dis 191:739–742

    Article  PubMed  CAS  Google Scholar 

  24. Hecht JL, Kadish AS, Jiang G (1995) Genetic characterization of human papillomavirus 18 E2 gene in clinical specimens suggests the presence of a subtype with decreased oncogenic potential. Int J Cancer 60:369–376

    Article  PubMed  CAS  Google Scholar 

  25. Lizano M, De la Cruz-Hernandez E, Carrillo-Garcia A, Garcia-Carranca A, Ponce-de-Leon-Rosales S, Duenas-Gonzalez A, Hernandez-Hernadez DM, Mohar A (2006) Distribution of HPV16 and 18 intratipic variants in normal cytology, intraepithelial lesions, and cervical cancer in a Mexican population. Gynecol Oncol 102:230–235

    Article  PubMed  Google Scholar 

  26. De la Cruz-Hernández E, García-Carrancá A, Mohar-Betancourt A, Dueñas-González A, Contreras-Paredes A, Pérez-Cardenas E, Herrera-Goepfert R, Lizano-Soberon M (2005) Differential splicing of E6 within human papillomavirus type 18 variants and functional consequences. J Gen Virol 86:2459–2468

    Article  Google Scholar 

  27. Demeret C, Yaniv M, Thierry F (1994) The E2 transcriptional repressor can compensate for SP1 activation of the human papillomavirus type 18 early promoter. J Virol 68:7075–7082

    PubMed  CAS  Google Scholar 

  28. Hidalgo A, Monroy A, Arana RM, Taja L, Vazquez G, Salcedo M (2003) Chromosomal imbalances in four new uterine cervix carcinoma derived cell lines. BMC Cancer 3:1–5

    Article  Google Scholar 

  29. Judge GG, Griffiths WE, Hill RC, Lûtkepoul H, Lee TC (1985) The theory and practice of econometrics, 2nd edn. Wiley, New York

  30. StataCorp (2005) Stata statistical software: release 9. StataCorp LP, College Station

  31. Siegel AF (1988) Statistics and data analysis an introduction. Wiley, New York

    Google Scholar 

  32. Arias-Pulido H, Peyton CL, Torres-Martinez N, Anderson DN, Wheeler CM (2005) Human papillomavirus type 18 variant lineages in United States populations characterized by sequence analysis of LCR-E6, E2, and L1 regions. Virology 338:22–34

    Article  PubMed  CAS  Google Scholar 

  33. Sichero L, Ferreira S, Trottier H, Duarte-Franco E, Ferenczy A, Franco EL, Villa LL (2007) High grade cervical lesions are caused preferentially by non-European variants of HPVs 16 and 18. Int J Cancer 120:1763–1768

    Article  PubMed  CAS  Google Scholar 

  34. De Bôer MA, Peters LA, Aziz MF, Siregar B, Cornain S, Vrede MA, Jordanova ES, Fleuren GJ (2005) Human papillomavirus type 18 variants: histopathology and E6/E7 polymorphisms in three countries. Int J Cancer 114:422–425

    Article  PubMed  Google Scholar 

  35. Watts KJ, Thompson CH, Cossart YE, Rose BR (2001) Variable oncogene promoter activity of human papillomavirus type 16 cervical cancer isolates from Australia. J Clin Microbiol 39:2009–2014

    Article  PubMed  CAS  Google Scholar 

  36. Meissner JD (1999) Nucleotide sequences and further characterization of human papillomavirus DNA present in the CasKi, SiHa and HeLa cervical carcinoma cell lines. J Gen Virol 80:1725–1733

    PubMed  CAS  Google Scholar 

  37. Caceres-Cortez JR, Alvarado-Moreno JA, Waga K, Rangel-Corona R, Monroy-Garcia A, Rocha-Zavaleta L, Urdiales-Ramos J, Weiss-Steider B, Haman A, Brousseau R, Hoang T (2001) Implication of tyrosine kinase receptor and steel factor in cell density-dependent growth in cervical cancers and leukemias. Cancer Res 61:6281–6289

    Google Scholar 

  38. Veress G, Szarka K, Dong XP, Gersely L, Pfister H (1999) Functional significance of sequence variation in the E2 gene and the long control region of human papillomavirus type 16. J Gen Virol 80:1035–1043

    PubMed  CAS  Google Scholar 

  39. Lee D, Lee B, Kim J, Kim DW, Choe J (2000) cAMP response element-binding protein-binding protein binds to human papillomvirus E2 protein and activates E2-dependant transcription. J Biol Chem 275:7045–7051

    Article  PubMed  CAS  Google Scholar 

  40. Steger G, Schnabel C, Schmidt HM (2002) The hinge region of the HPV type 8 E2 protein activates the human p21WAF1/CIP1 promoter via interaction with Sp1. J Gen Virol 83:503–510

    PubMed  Google Scholar 

  41. Hadaschik D, Hinterkeuser K, Oldak M, Pfister HJ, Smola-Hess S (2003) The Papillomavirus E2 protein binds to and synergizes with C/EBP factors involved in keratinocyte differentiation. J Virol 77:5253–5265

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was partially supported by Consejo Nacional de Ciencia y Tecnología/Fondos Sectoriales y Mixtos SALUD-2004-01-067 and CB 60722. We thank Françoise Thierry for her support at the initial steps of this work.

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Authors and Affiliations

  1. Unit of Biomedical Research in Cancer, National Cancer Institute, 14080, Mexico City, Mexico

    Alejandro López-Saavedra, Alejandro García-Carrancá, Alejandro Mohar & Marcela Lizano

  2. Biomedical Research Institute, National Autonomous University of Mexico, Av. San Fernando No. 22, Tlalpan, 14080, Mexico City, Mexico

    Alejandro López-Saavedra, Alejandro García-Carrancá, Alejandro Mohar & Marcela Lizano

  3. College of Pharmacy, Autonomous University of Morelos, Cuernavaca, Mexico

    Leticia González-Maya

  4. Clinical Epidemiology Unit, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

    Sergio Ponce-de-León

Authors
  1. Alejandro López-Saavedra
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  2. Leticia González-Maya
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  3. Sergio Ponce-de-León
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  4. Alejandro García-Carrancá
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  5. Alejandro Mohar
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  6. Marcela Lizano
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Correspondence to Marcela Lizano.

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López-Saavedra, A., González-Maya, L., Ponce-de-León, S. et al. Functional implication of sequence variation in the long control region and E2 gene among human papillomavirus type 18 variants. Arch Virol 154, 747–754 (2009). https://doi.org/10.1007/s00705-009-0362-4

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  • DOI: https://doi.org/10.1007/s00705-009-0362-4

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