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Decreased p21 Expression in HPV-18 Positive Cervical Carcinomas

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Pathology & Oncology Research

Abstract

The aim of this study was to investigate the relationship between different human papillomaviruse (HPV) genotypes and the expression of p53, p21 and p27 in cervical carcinomas. A total of 103 cases of cervical carcinomas were assayed for expression of p53, p21 and p27 by immunohistochemistry. HPV typing was carried out by two polymerase chain reaction-based methods. Overall, HPV prevalence was 97.1% among the cervical carcinomas in this study. HPV-16 was detected in 66% of the tumors, HPV-18 in 7.8%, HPV-16/18 in 7.8% and other HPV types in 15.5%. The expression of p53 and p27 was not related to HPV genotype. However, in the HPV-18 positive cervical carcinomas, expression of p21 was significantly decreased or completely absent (P = 0.019). Our results indicated that down-regulation of p21 was strongly associated with HPV-18 positive cervical carcinomas. The significantly lower expression of p21 protein in HPV-18 positive samples compared to HPV-18 negative cervical carcinomas supports the hypothesis that inactivation and degradation of p21 proteins by HPV-18 E7 may play an important role in the carcinogenesis of HPV-18 positive cervical neoplasia.

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References

  1. Walboomers JMM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJF, Peto J, Meijer CJLM, Munoz N (1999) Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189:12–19

    Article  CAS  PubMed  Google Scholar 

  2. Hawley-Nelson P, Vousden KH, Hubbert NL, Lowy DR, Schiller JT (1989) HPV16 E6 and E7 proteins cooperate to immortalize human foreskin keratinocytes. EMBO J 8:3905–3910

    CAS  PubMed  Google Scholar 

  3. Galloway DA, McDougall JK (1996) The disruption of cell cycle checkpoints by papillomavirus oncoproteins contributes to anogenital neoplasia. Semin Cancer Biol 7:309–315

    Article  CAS  PubMed  Google Scholar 

  4. zur Hausen H (2000) Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst 92:690–698

    Article  PubMed  Google Scholar 

  5. Chen YQ, Cipriano SC, Arenkiel JM, Miller FR (1995) Tumor suppression by p21WAF1. Cancer Res 55:4536–4539

    CAS  PubMed  Google Scholar 

  6. Costa MJ, Hansen CL, Walls JE, Scudder SA (1999) Immunohistochemical markers of cell cycle control applied to ovarian and primary peritoneal surface epithelial neoplasms: p21WAF1/CIP1 predicts survival and good response to platinin-based chemotherapy. Hum Pathol 30:640–647

    Article  CAS  PubMed  Google Scholar 

  7. Ropponen KM, Kellokoski JK, Lipponen PK, Pietilainen T, Eskelinen MJ, Alhava EM, Kosma VM (1999) p21/WAF1 expression in human colorectal carcinoma: association with p53, transcription factor AP-2 and prognosis. Br J Cancer 81:133–140

    Article  CAS  PubMed  Google Scholar 

  8. Ogawa M, Maeda K, Onoda N, Chung YS, Sowa M (1997) Loss of p21 WAF1/CIP1 expression correlates with disease progression in gastric carcinoma. Br J Cancer 75:1617–1620

    CAS  PubMed  Google Scholar 

  9. Nakayama K, Ishida N, Shirane M, Inomata A, Inoue T, Shishido N, Horii I, Loh DY, Nakayama KI (1996) Mice lacking p27Kip1 display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 85:707–720

    Article  CAS  PubMed  Google Scholar 

  10. Troncone G, Vetrani A, Rosa GD, Gerbasio D, Palombini L (1999) Cyclin dependent kinase inhibitor p27Kip1 expression in normal and neoplastic cervical epithelium. J Clin Pathol 52:880–887

    Article  CAS  PubMed  Google Scholar 

  11. Kim YT, Choi EK, Cho NH, Ko JH, Yang WI, Kim JW, Lee SH (2000) Expression of cyclin E and p27KIP1 in cervical carcinoma. Cancer Lett 153:41–50

    Article  Google Scholar 

  12. Levine AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88:323–331

    Article  CAS  PubMed  Google Scholar 

  13. El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B (1993) WAF1, a potential mediator of p53 tumor suppressor. Cell 75:817–825

    Article  CAS  PubMed  Google Scholar 

  14. Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253:49–53

    Article  CAS  PubMed  Google Scholar 

  15. Woodman CB, Collins S, Rollason TP, Winter H, Bailey A, Yates M et al (2003) Human papillomavirus type 18 and rapidly progressing cervical intraepithelial neoplasia. Lancet 361:40–43

    Article  PubMed  Google Scholar 

  16. Liaw KL, Glass AG, Manos MM, Greer CE, Scott DR, Sherman M et al (1999) Detection of human papillomavirus DNA in cytologically normal women and subsequent cervical squamous intraepithelial lesions. J Natl Cancer Inst 91:954–960

    Article  CAS  PubMed  Google Scholar 

  17. Londesborough P, Ho L, Terry G, Cuzick J, Wheeler C, Singer A (1996) Human papillomavirus genotype as a predictor of persistence and development of high-grade lesions in women with minor cervical abnormalities. Int J Cancer 69:364–368

    Article  CAS  PubMed  Google Scholar 

  18. Huang LW, Chao SL, Hwang JL, Chou YY (2002) Down-regulation of p27 is associated with malignant transformation and aggressive phenotype of cervical neoplasms. Gynecol Oncol 85:524–528

    Article  CAS  PubMed  Google Scholar 

  19. Huang LW, Chou YY, Chao SL, Chen TJ, Lee TT (2001) p53 and p21 expression in precancerous lesions and carcinomas of the uterine cervix: overexpression of p53 predicts poor disease outcome. Gynecol Oncol. 83:348–354

    Article  CAS  PubMed  Google Scholar 

  20. 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  CAS  PubMed  Google Scholar 

  21. Funk JO, Waga S, Harry JB, Espling E, Stillman B, Galloway DA (1997) Inhibition of CDK activity and PCNA-dependent DNA replication by p21 is blocked by interaction with the HPV-16 E7 oncoprotein. Genes Dev 11:2090–2100

    Article  CAS  PubMed  Google Scholar 

  22. Zerfass-Thome K, Zwerschke W, Mannhardt B, Tindle R, Botz JW, Jansen-Durr P (1996) Inactivation of the cdk inhibitor p27KIP1 by the human papillomavirus type 16 E7 oncoprotein. Oncogene. 13:2323–2330

    CAS  PubMed  Google Scholar 

  23. Huang LW, Chao SL, Chen PH, Chou HP (2004) Multiple HPV genotypes in cervical carcinomas: improved DNA detection and typing in archival tissues. J Clin Virol 29:271–276

    Article  CAS  PubMed  Google Scholar 

  24. Lorincz AT, Reid R, Jenson AB, Greenberg MD, Lancaster W, Kurman RJ (1992) Human papillomavirus infection of the cervix: relative risk associations of 15 common anogenital types. Obstet Gynecol 79:328–337

    Article  CAS  PubMed  Google Scholar 

  25. Lie AK, Skarsvag S, Skomedal H, Haugen OA, Holm R (1999) Expression of p53, MDM2, and p21 proteins in high-grade cervical intraepithelial neoplasia and relationship to human papillomavirus infection. Int J Gynecol Pathol 18:5–11

    Article  CAS  PubMed  Google Scholar 

  26. Cavuslu S, Goodlad J, Hobbs C, Connor AM, Raju KS, Best JM, Cason J (1997) Relationship between human papillomavirus infection and overexpression of p53 protein in cervical carcinomas and lymph node metastases. J Med Virol 53:111–117

    Article  CAS  PubMed  Google Scholar 

  27. Michieli P, Chedid M, Lin D, Pierce JH, Mercer WE, Givol D (1994) Induction of WAF1/CIP1 by a p53-independent Pathway. Cancer Res 54:3391–3395

    CAS  PubMed  Google Scholar 

  28. Parker SB, Eichele G, Zhang P, Rawls A, Sands AT, Bradley A, Olson EN, Harper JW, Elledge SJ (1995) p53-independent expression of p21Cip1 in muscle and other terminally differentiating cells. Science 267:1024–1027

    Article  CAS  PubMed  Google Scholar 

  29. Jones DL, Alani RM, Munger K (1997) The human papillomavirus E7 oncoprotein can uncouple cellular differentiation and proliferation in human keratinocytes by abrogating p21Cip1-mediated inhibition of cdk2. Genes Dev 11:2101–2111

    Article  CAS  PubMed  Google Scholar 

  30. Rangarajan A, Talora C, Okuyama R, Nicolas M, Mammucari C, Oh H, Aster JC, Krishna S, Metzger D, Chambon P, Miele L, Aguet M, Radtke F, Dotto GP (2001) Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J. 20:3427–3436

    Article  CAS  PubMed  Google Scholar 

  31. Werness BA, Wang HQ, Chance J, Goldstein DJ (1997) p53-independent expression of p21waf1/cip1 in preinvasive and invasive squamous neoplasms of the uterine cervix. Mod Pathol 10:578–584

    CAS  PubMed  Google Scholar 

  32. Nadal A, Jares P, Cazorla M, Fernández PL, Sanjuan X, Hernandez L, Pinyol M, Aldea M, Mallofré C, Muntané J, Traserra J, Campo E, Cardesa A (1997) p21WAF1/Cip1 expression is associated with cell differentiation but not with p53 mutations in squamous cell carcinomas of the larynx. J Pathol 183:156–163

    Article  CAS  PubMed  Google Scholar 

  33. 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  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by a research grant (SKH-8302-97-DR-20) from the Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Shin Kong Wu Ho-Su Memorial Hospital, 95 Wen Chang Road, Shih-Lin District, Taipei, 111, Taiwan

    Lee-Wen Huang, Kok-Min Seow, Yu-Hung Lin, Hun-Shan Pan & Heng-Ju Chen

  2. College of Medicine, Fu Jen Catholic University, Hsinchuang, Taipei Hsien, Taiwan

    Lee-Wen Huang, Kok-Min Seow, Yu-Hung Lin, Hun-Shan Pan & Heng-Ju Chen

  3. College of Medicine, Taipei Medical University, Taipei, Taiwan

    Lee-Wen Huang & Chin-Cheng Lee

  4. Department of Pathology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan

    Chin-Cheng Lee

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  1. Lee-Wen Huang
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Correspondence to Lee-Wen Huang.

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Huang, LW., Seow, KM., Lee, CC. et al. Decreased p21 Expression in HPV-18 Positive Cervical Carcinomas. Pathol. Oncol. Res. 16, 81–86 (2010). https://doi.org/10.1007/s12253-009-9191-8

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  • DOI: https://doi.org/10.1007/s12253-009-9191-8

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