Tumor Biology

, Volume 34, Issue 3, pp 1801–1806

Cell growth inhibition in HPV 18 positive uveal melanoma cells by E6/E7 siRNA

Research Article

Abstract

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. However, the molecular development of UM is not fully understood and current therapeutic modalities result in poor outcomes. Increasingly, data have shown that human papillomaviruses (HPVs) contribute to the development of cervical cancer and other malignancies, and the key viral oncoprotein E6/E7 has become the target of gene therapy in HPV-related cancers. In this study, we identified HPV 18 infection in the UM cell line, VUP, for the first time and silenced HPV 18 E6/E7 expression using siRNA. Our results demonstrated that down regulation of HPV 18E6/E7 led to growth inhibition and cell cycle block in VUP cells by activation of the p53 and Rb pathways. We propose that HPV is possibly involved in the development of UM, and provide a novel target for the development of therapeutic strategies for UM.

Keywords

Uveal melanoma Human papillomavirus 18 E6 E7 siRNA 

References

  1. 1.
    Singh AD. Metastatic uveal melanoma. Ophthalmol Clin North Am. 2005;18:143–50. ix.PubMedCrossRefGoogle Scholar
  2. 2.
    Singh AD. Survival rates with uveal melanoma in the United States: 1973–1997. Ophthalmology. 2003;110:962–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Landreville S. Emerging insights into the molecular pathogenesis of uveal melanoma. Future Oncol. 2008;4:629–36.PubMedCrossRefGoogle Scholar
  4. 4.
    Papastefanou VP. Uveal melanoma. J Skin Cancer. 2011;2011:573974.PubMedGoogle Scholar
  5. 5.
    Lassen P. The role of human papillomavirus in head and neck cancer and the impact on radiotherapy outcome. Radiother Oncol. 2010;95:371–80.PubMedCrossRefGoogle Scholar
  6. 6.
    Michl P. Human papillomavirus in the etiology of head and neck carcinomas. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2010;154:9–12.PubMedCrossRefGoogle Scholar
  7. 7.
    IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Human papillomaviruses. IARC Monogr Eval Carcinog Risks Hum. 1995;64:1–378.Google Scholar
  8. 8.
    zur Hause H. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer. 2002;2:342–50.CrossRefGoogle Scholar
  9. 9.
    Anand B. Prevalence of high-risk human papillomavirus genotypes in retinoblastoma. Br J Ophthalmol. 2011;95:1014–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Shetty OA. Evidence for the presence of high risk human papillomavirus in retinoblastoma tissue from nonfamilial retinoblastoma in developing countries. Pediatr Blood Cancer. 2012;58:185–90.PubMedCrossRefGoogle Scholar
  11. 11.
    Tornesello ML. Evaluating the role of human papillomaviruses in conjunctival neoplasia. Br J Cancer. 2006;94:446–9.PubMedCrossRefGoogle Scholar
  12. 12.
    zur Hausen H. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst. 2000;92:690–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Gu W. Inhibition of cervical cancer cell growth in vitro and in vivo with lentiviral-vector delivered short hairpin RNA targeting human papillomavirus E6 and E7 oncogenes. Cancer Gene Ther. 2006;13:1023–32.PubMedCrossRefGoogle Scholar
  14. 14.
    Chen L. Down-regulation of HPV18 E6, E7, or VEGF expression attenuates malignant biological behavior of human cervical cancer cells. Med Oncol. 2011;28 Suppl 1:528–39.PubMedGoogle Scholar
  15. 15.
    Kuner R. Identification of cellular targets for the human papillomavirus E6 and E7 oncogenes by RNA interference and transcriptome analyses. J Mol Med (Berl). 2007;85:1253–62.CrossRefGoogle Scholar
  16. 16.
    Chang JT. Highly potent and specific siRNAs against E6 or E7 genes of HPV16- or HPV18-infected cervical cancers. Cancer Gene Ther. 2010;17:827–36.PubMedCrossRefGoogle Scholar
  17. 17.
    Boulet G. Human papillomavirus: E6 and E7 oncogenes. Int J Biochem Cell Biol. 2007;39:2006–11.PubMedCrossRefGoogle Scholar
  18. 18.
    El-Deiry WS. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993;75:817–25.PubMedCrossRefGoogle Scholar
  19. 19.
    Sherr CJ. The Pezcoller lecture: cancer cell cycles revisited. Cancer Res. 2000;60:3689–95.PubMedGoogle Scholar
  20. 20.
    Psyrri A. Human papillomavirus in cervical and head-and-neck cancer. Nat Clin Pract Oncol. 2008;5:24–31.PubMedCrossRefGoogle Scholar
  21. 21.
    Rampias T. E6 and e7 gene silencing and transformed phenotype of human papillomavirus 16-positive oropharyngeal cancer cells. J Natl Cancer Inst. 2009;101:412–23.PubMedCrossRefGoogle Scholar
  22. 22.
    Wang X. Small interfering RNA for effective cancer therapies. Mini Rev Med Chem. 2011;11:114–24.PubMedCrossRefGoogle Scholar
  23. 23.
    Yamato K. Induction of cell death in human papillomavirus 18-positive cervical cancer cells by E6 siRNA. Cancer Gene Ther. 2006;13:234–41.PubMedCrossRefGoogle Scholar
  24. 24.
    DeFilippis RA. Endogenous human papillomavirus E6 and E7 proteins differentially regulate proliferation, senescence, and apoptosis in HeLa cervical carcinoma cells. J Virol. 2003;77:1551–63.PubMedCrossRefGoogle Scholar
  25. 25.
    Horner SM. Repression of the human papillomavirus E6 gene initiates p53-dependent, telomerase-independent senescence and apoptosis in HeLa cervical carcinoma cells. J Virol. 2004;78:4063–73.PubMedCrossRefGoogle Scholar
  26. 26.
    Sima N. RNA interference against HPV16 E7 oncogene leads to viral E6 and E7 suppression in cervical cancer cells and apoptosis via upregulation of Rb and p53. Apoptosis. 2008;13:273–81.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Biyun Cun
    • 1
  • Xin Song
    • 1
  • Renbing Jia
    • 1
  • Haibo Wang
    • 1
  • Xiaoping Zhao
    • 1
  • Bo Liu
    • 1
  • Shengfang Ge
    • 1
  • Xianqun Fan
    • 2
  1. 1.Department of Ophthalmology, Ninth People’s HospitalShanghai Jiaotong University School of MedicineShanghaiChina
  2. 2.Department of Ophthalmology, Ninth People’s HospitalShanghai Jiaotong University School of MedicineShanghaiPeople’s Republic of China

Personalised recommendations