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HPV16 E5 peptide vaccine in treatment of cervical cancer in vitro and in vivo

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Summary

Human papillomavirus (HPV)-induced cervical cancer is the second most common cancer among women worldwide. Despite the encouraging development of the preventive vaccine for HPV, a vaccine for both prevention and therapy or pre-cancerous lesions remains in high priority. Thus far, most of the HPV therapeutic vaccines are focused on HPV E6 and E7 oncogene. However these vaccines could not completely eradicate the lesions. Recently, HPV E5, which is considered as an oncogene, is getting more and more attention. In this study, we predicted the epitopes of HPV16 E5 by bioinformatics as candidate peptide, then, evaluated the efficacy and chose an effective one to do the further test. To evaluate the effect of vaccine, rTC-1 (TC-1 cells infected by rAAV-HPV16E5) served as cell tumor model and rTC-1 loading mice as an ectopic tumor model. We prepared vaccine by muscle injection. The vaccine effects were determined by evaluating the function of tumor-specific T cells by cell proliferation assay and ELISPOT, calculating the tumor volume in mice and estimating the survival time of mice. Our in vitro and in vivo studies revealed that injection of E5 peptide+CpG resulted in strong cell-mediated immunity (CMI) and protected mice from tumor growth, meanwhile, prolonged the survival time after tumor cell loading. This study provides new insights into HPV16 E5 as a possible target on the therapeutic strategies about cervical cancer.

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References

  1. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol, 1999,189(1):12–19

    Article  PubMed  CAS  Google Scholar 

  2. Bell MC, Alvarez RD. Chemoprevention and vaccines: a review of the nonsurgical options for the treatment of cervical dysplasia. Int J Gynecol Cancer, 2005,15(1):4–12

    Article  PubMed  CAS  Google Scholar 

  3. Mahdavi A, Monk BJ. Vaccines against human papillomavirus and cervical cancer: promises and challenges. Oncologist, 2005,10(7):528–538

    Article  PubMed  CAS  Google Scholar 

  4. Jansen KU, Shaw AR. Human papillomavirus vaccines and prevention of cervical cancer. Annu Rev Med, 2004,55(1):319–331

    Article  PubMed  CAS  Google Scholar 

  5. Sarkar AK, Tortolero-Luna G, Follen M, et al. Inverse correlation of cellular immune responses specific to synthetic peptides from the E6 and E7 oncoproteins of HPV-16 with recurrence of cervical intraepithelial neoplasia in a cross-sectional study. Gynecol Oncol, 2005,99(3):S251–261

    Article  PubMed  CAS  Google Scholar 

  6. Ji H, Chang EY, Lin KY, et al. Antigen-specific immunotherapy for murine lung metastatic tumors expressing human papillomavirus type 16 E7 oncoprotein. Int J Cancer, 1998,78(1):41–45

    Article  PubMed  CAS  Google Scholar 

  7. Tsai TC, Chen SL. The biochemical and biological functions of human papillomavirus type 16 E5 protein. Arch Virol, 2003,148(8):1445–1453

    Article  PubMed  CAS  Google Scholar 

  8. Nath R, Mant CA, Kell B, et al. Analyses of variant human papillomavirus type-16 E5 proteins for their ability to induce mitogenesis of murine fibroblasts. Cancer Cell Int, 2006,6(1):19–27

    Article  PubMed  Google Scholar 

  9. Krawczyk E, Suprynowicz FA, Sudarshan SR, et al. Membrane orientation of the human papillomavirus type 16 E5 oncoprotein. J Virol, 2010,84(4):1696–1703

    Article  PubMed  CAS  Google Scholar 

  10. Kivi N, Greco D, Auvinen P, et al. Genes involved in cell adhesion, cell motility and mitogenic signaling are altered due to HPV 16 E5 protein expression. Oncogene, 2008,27(18):2532–2541

    Article  PubMed  CAS  Google Scholar 

  11. Pedroza-Saavedra A, Lam EW, Esquivel-Guadarrama F, et al. The human papillomavirus type 16 E5 oncoprotein synergizes with EGF-receptor signaling to enhance cell cycle progression and the down-regulation of p27(Kip1). Virology, 2010,400(1):44–52

    Article  PubMed  CAS  Google Scholar 

  12. Stöppler MC, Straight SW, Tsao G, et al. The E5 gene of HPV-16 enhances keratinocyte immortalization by full-length DNA. Virology, 1996,223(1):251–254

    Article  PubMed  Google Scholar 

  13. Gao P, Zheng J. High-risk HPV E5-induced cell fusion: a critical initiating event in the early stage of HPV-associated cervical cancer. Virol J, 2010,7(1):238–240

    Article  PubMed  Google Scholar 

  14. Boulenouar S, Weyn C, Van Noppen M, et al. Effects of HPV-16 E5, E6 and E7 proteins on survival, adhesion, migration and invasion of trophoblastic cells. Carcinogenesis, 2010,31(3):473–480

    Article  PubMed  CAS  Google Scholar 

  15. Liao SJ, Deng DR, Hu XJ, et al. HPV16/18 E5, a promising candidate for cervical cancer vaccines, affects SCPs, cell proliferation and cell cycle, and forms a potential network with E6 and E7. Int J Mol Med, 2013,31(1): 120–128

    PubMed  CAS  Google Scholar 

  16. Klinman DM, Currie D, Gursel I, et al. Use of CpG oligodeoxynucleotides as immune adjuvants. Immunol Rev, 2004,199(1):201–216

    Article  PubMed  CAS  Google Scholar 

  17. Vazquez-Ortiz G, Ciudad CJ, Pina P, et al. Gene identification by cDNA arrays in HPV-positive cervical cancer. Arch Med Res, 2005,36(5):448–458

    Article  PubMed  CAS  Google Scholar 

  18. Parker KC, Bednarek MA, Coligan JE. Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. J Immunol, 1994,152(1):163–175

    PubMed  CAS  Google Scholar 

  19. Rammensee H, Bachmann J, Emmerich NP, et al. SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics, 1999,50(3–4):213–219

    Article  PubMed  CAS  Google Scholar 

  20. Bhasin M, Raghava GP. Analysis and prediction of affinity of TAP binding peptides using cascade SVM. Protein Sci, 2004,13(3):596–607

    Article  PubMed  CAS  Google Scholar 

  21. Singh H, Raghava GP. ProPred1: prediction of promiscuous MHC Class-I binding sites. Bioinformatics, 2003,19(8):1009–1014

    Article  PubMed  CAS  Google Scholar 

  22. Samorski R, Gissmann L, Osen W. Codon optimized expression of HPV 16 E6 renders target cells susceptible to E6-specific CTL recognition. Immunol Lett, 2006,107(1):41–49

    Article  PubMed  CAS  Google Scholar 

  23. Daftarian P, Mansour M, Benoit AC, et al. Eradication of established HPV 16-expressing tumors by a single administration of a vaccine composed of a liposome-encapsulated CTL-T helper fusion peptide in a water-in-oil emulsion. Vaccine, 2006,24(24):5235–5244

    Article  PubMed  CAS  Google Scholar 

  24. Kozak M. At least six nucleotides preceding the AUG initiator codon enhance translation in mammalian cells. J Mol Biol, 1987,196(4):947–950

    Article  PubMed  CAS  Google Scholar 

  25. Xiao X, Li J, Samulski RJ. Production of high-titer recombinant adeno-associated virus vectors in the absence of helper adenovirus. J Virol, 1998,72(3):2224–2232

    PubMed  CAS  Google Scholar 

  26. Xiao X, Li J, Samulski RJ. Efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector. J Virol, 1996,70(11):8098–8108

    PubMed  CAS  Google Scholar 

  27. Chen Y, Xiong T, Yu L, et al. Whole-body fluorescent optical imaging based on power light emitting diode. Conf Proc IEEE Eng Med Biol Soc, 2005,2(1):1442–1445

    PubMed  Google Scholar 

  28. Kim TY, Myoung HJ, Kim JH, et al. Both E 7 and CpG-oligodeoxynucleotide are required for protective immunity against challenge with human papillomavirus 16 (E6/E7) immortalized tumor cells: involvement of CD4+ and CD8+ T cells in protection. Cancer Res, 2002,62(24):7234–7240

    PubMed  CAS  Google Scholar 

  29. Cools N, Ponsaerts P, Lenjou M, et al. Sensitive detection of human papillomavirus type 16 E7-specific T cells by ELISPOT after multiple in vitro stimulations of CD8+ T cells with peptide-pulsed autologous dendritic cells. Mol Cancer, 2006,5(1):49–56

    Article  PubMed  Google Scholar 

  30. Chen YF, Lin CW, Tsao YP, et al. Cytotoxic-T-lympho-cyte human papillomavirus type 16 E5 peptide with CpG-oligodeoxynucleotide can eliminate tumor growth in C57BL/6 mice. J Virol, 2004,78(3):1333–1343

    Article  PubMed  CAS  Google Scholar 

  31. Frazer IH. Prevention of cervical cancer through papillomavirus vaccination. Nat Rev Immunol, 2004,4(1): 46–54

    Article  PubMed  CAS  Google Scholar 

  32. Chang JL, Tsao YP, Liu DW, et al. The expression of HPV-16 E5 protein in squamous neoplastic changes in the uterine cervix. J Biomed Sci, 2001,8(2):206–213

    Article  PubMed  CAS  Google Scholar 

  33. Lowy DR, Schiller JT. Prophylactic human papillomavirus vaccines. J Clin Invest, 2006,116(5):1167–1173

    Article  PubMed  CAS  Google Scholar 

  34. Peng S, Tomson TT, Trimble C, et al. A combination of DNA vaccines targeting human papillomavirus type 16 E6 and E7 generates potent antitumor effects. Gene Ther, 2006,13(3):257–265

    Article  PubMed  CAS  Google Scholar 

  35. Liao SJ, Deng DR, Zhang WN, et al. Human papillomavirus 16/18 E5 promotes cervical cancer cell proliferation, migration and invasion in vitro and accelerates tumor growth in vivo. Oncol Rep, 2013,29(1):95–102

    PubMed  CAS  Google Scholar 

  36. Bouvard V, Matlashewski G, Gu ZM, et al. The human papillomavirus type 16 E5 gene cooperates with the E7 gene to stimulate proliferation of primary cells and increases viral gene expression. Virology, 1994,203(1): 73–80

    Article  PubMed  CAS  Google Scholar 

  37. Gao P, Zheng J. High-risk HPV E5-induced cell fusion: a critical initiating event in the early stage of HPV-associated cervical cancer. Virol J, 2010,7(1):238–240

    Article  PubMed  Google Scholar 

  38. Zwaveling S, Ferreira Mota SC, Nouta J, et al. Established human papillomavirus type 16-expressing tumors are effectively eradicated following vaccination with long peptides. J Immunol, 2002,169(1):350–358

    PubMed  CAS  Google Scholar 

  39. Neves PC, Rudersdorf RA, Galler R, et al. CD8+ gamma-delta TCR+ and CD4+ T cells produce IFN-gamma at 5-7 days after yellow fever vaccination in Indian rhesus macaques, before the induction of classical antigen-specific T cell responses. Vaccine, 2010,28(51): 8183–8188

    Article  PubMed  CAS  Google Scholar 

  40. Kim MK, Kim HS, Kim SH, et al. Human papillomavirus type 16 E5 oncoprotein as a new target for cervical cancer treatment. Biochem Pharmacol, 2010,80(12):1930–1935

    Article  PubMed  CAS  Google Scholar 

  41. Li K, Jin X, Fang Y, et al. Correlation between physical status of human papilloma virus and cervical carcinogenesis. J Huazhong Univ Sci Technol [Med Sci], 2012,32(1):97–102

    Article  Google Scholar 

  42. Maufort JP, Shai A, Pitot HC, et al. A role for HPV16 E5 in cervical carcinogenesis. Cancer Res, 2010,70(7):2924–2931

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Shu-jie Liao  (廖书杰), Dong-rui Deng  (邓东锐), Dan Zeng  (曾 丹), Ling Zhang  (张 玲), Wei-na Zhang  (张维娜), Li Li  (李 莉), Xue-feng Jiang  (蒋学峰), Chang-yu Wang  (王常玉), Jian-feng Zhou  (周剑锋), Shi-xuan Wang  (王世宣), Han-wang Zhang  (章汉旺) & Ding Ma  (马 丁)

  2. Department of Obstetrics and Gynaecology, Wuhan General Hospital of Guangzhou Military Region, Wuhan, 430070, China

    Xiao-ji Hu  (胡晓继)

Authors
  1. Shu-jie Liao  (廖书杰)
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  2. Dong-rui Deng  (邓东锐)
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  3. Dan Zeng  (曾 丹)
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  4. Ling Zhang  (张 玲)
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  5. Xiao-ji Hu  (胡晓继)
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  6. Wei-na Zhang  (张维娜)
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  7. Li Li  (李 莉)
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  8. Xue-feng Jiang  (蒋学峰)
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  10. Jian-feng Zhou  (周剑锋)
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  11. Shi-xuan Wang  (王世宣)
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  12. Han-wang Zhang  (章汉旺)
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  13. Ding Ma  (马 丁)
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Corresponding authors

Correspondence to Han-wang Zhang  (章汉旺) or Ding Ma  (马 丁).

Additional information

This project was supported by the grants from 973 National Great Foundation Research Program of China (No. 2009CB 521808), National Natural Sciences Foundation of China (No. 30901586, 81170619, 81172464 and 81372804), Huibei Province Science Foundation of China (No. 2011CDB191) and Central University Basic Science Research Fund of China (No. 2012QN188).

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Liao, Sj., Deng, Dr., Zeng, D. et al. HPV16 E5 peptide vaccine in treatment of cervical cancer in vitro and in vivo . J. Huazhong Univ. Sci. Technol. [Med. Sci.] 33, 735–742 (2013). https://doi.org/10.1007/s11596-013-1189-5

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  • DOI: https://doi.org/10.1007/s11596-013-1189-5

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