Skip to main content

Advertisement

SpringerLink
Log in

Effect of HPV on tumor expression levels of the most commonly used markers in HNSCC

  • Original Article
  • Published:
Tumor Biology

Abstract

Approximately 90 % of head and neck cancers are squamous cell carcinomas (HNSCC), and the overall 5-year survival rate is not higher than 50 %. There is much evidence that human papillomavirus (HPV) infection may influence the expression of commonly studied HNSCC markers. Our study was focused on the possible HPV-specificity of molecular markers that could be key players in important steps of cancerogenesis (MKI67, EGF, EGFR, BCL-2, BAX, FOS, JUN, TP53, MT1A, MT2A, VEGFA, FLT1, MMP2, MMP9, and POU5F). qRT-PCR analysis of these selected genes was performed on 74 biopsy samples of tumors from patients with histologically verified HNSCC (22 HPV–, 52 HPV+). Kaplan-Meier analysis was done to determine the relevance of these selected markers for HNSCC prognosis. In conclusion, our study confirms the impact of HPV infection on commonly studied HNSCC markers MT2A, MMP9, FLT1, VEGFA, and POU5F that were more highly expressed in HPV-negative HNSCC patients and also shows the relevance of studied markers in HPV-positive and HPV-negative HNSCC patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Kim L, King T, Agulnik M. Head and neck cancer: changing epidemiology and public health implications. Oncol-New York. 2010;24(10):915–24.

    Google Scholar 

  2. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. Ca-a Cancer J Clin. 2015;65(2):87–108. doi:10.3322/caac.21262.

    Article  Google Scholar 

  3. Syrjanen K, Syrjanen S, Lamberg M, Pyrhonen S, Nuutinen J. Morphological and immunohistochemical evidence suggesting human papillomavirus (HPV) involvement in oral squamous-cell carcinogenesis. Int J Oral Surg. 1983;12(6):418–24. doi:10.1016/s0300-9785(83)80033-7.

    Article  CAS  PubMed  Google Scholar 

  4. Marur S, D’Souza G, Westra WH, Forastiere AA. HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet Oncol. 2010;11(8):781–9. doi:10.1016/s1470-2045(10)70017-6.

    Article  PubMed  Google Scholar 

  5. Slebos RJC, Yi YJ, Ely K, Carter J, Evjen A, Zhang XQ, et al. Gene expression differences associated with human papillomavirus status in head and neck squamous cell carcinoma. Clin Cancer Res. 2006;12(3):701–9. doi:10.1158/1078-0432.ccr-05-2017.

    Article  CAS  PubMed  Google Scholar 

  6. Haedicke J, Iftner T. Human papillomaviruses and cancer. Radiother Oncol. 2013;108(3):397–402. doi:10.1016/j.radonc.2013.06.004.

    Article  CAS  PubMed  Google Scholar 

  7. Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomark Prev. 2005;14(2):467–75. doi:10.1158/1055-9965.epi-04-0551.

    Article  CAS  Google Scholar 

  8. Ajiro M, Zheng Z-M. Oncogenes and RNA splicing of human tumor viruses. Emerging Microbes Infect. 2014;3:e63. doi:10.1038/emi.2014.62.

    Article  CAS  Google Scholar 

  9. Polanska H, Raudenska M, Gumulec J, Sztalmachova M, Adam V, Kizek R, et al. Clinical significance of head and neck squamous cell cancer biomarkers. Oral Oncol. 2014;50(3):168–77. doi:10.1016/j.oraloncology.2013.12.008.

    Article  CAS  PubMed  Google Scholar 

  10. Mantovani F, Banks L. The human papillomavirus E6 protein and its contribution to malignant progression. Oncogene. 2001;20(54):7874–87. doi:10.1038/sj.onc.1204869.

    Article  CAS  PubMed  Google Scholar 

  11. Braakhuis BJM, Snijders PJF, Keune WJH, Meijer C, Ruijter-Schippers HJ, Leemans CR, et al. Genetic patterns in head and neck cancers that contain or lack transcriptionally active human papillomavirus. J Natl Cancer Inst. 2004;96(13):998–1006. doi:10.1093/jnci/djh183.

    Article  CAS  PubMed  Google Scholar 

  12. Jo S, Juhasz A, Zhang K, Ruel C, Loera S, Wilczynski SP, et al. Human papillomavirus infection as a prognostic factor in oropharyngeal squamous cell carcinomas treated in a prospective phase II clinical trial. Anticancer Res. 2009;29(5):1467–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Ritchie JM, Smith EM, Summersgill KF, Hoffman HT, Wang DH, Klussmann JP, et al. Human papillomavirus infection as a prognostic factor in carcinomas of the oral cavity and oropharynx. Int J Cancer. 2003;104(3):336–44. doi:10.1002/ijc.10960.

    Article  CAS  PubMed  Google Scholar 

  14. Lajer CB, von Buchwald C. The role of human papillomavirus in head and neck cancer. APMIS. 2010;118(6-7):510–9. doi:10.1111/j.1600-0463.2010.02624.x.

    Article  CAS  PubMed  Google Scholar 

  15. D’Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch WM, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356(19):1944–56. doi:10.1056/NEJMoa065497.

    Article  PubMed  Google Scholar 

  16. Gillison ML, D’Souza G, Westra W, Sugar E, Xiao WH, Begum S, et al. Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst. 2008;100(6):407–20. doi:10.1093/jnci/djn025.

    Article  PubMed  Google Scholar 

  17. Nasman A, Attner P, Hammarstedt L, Do J, Eriksson M, Giraud G, et al. Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma? Int J Cancer. 2009;125(2):362–6. doi:10.1002/ijc.24339.

    Article  CAS  PubMed  Google Scholar 

  18. Kim K-Y, Zhang X, Cha I-H. Identification of human papillomavirus status specific biomarker in head and neck cancer. Head Neck-J Sci Spec Head Neck. 2015;37(9):1310–8. doi:10.1002/hed.23751.

    Article  Google Scholar 

  19. Schlecht NF, Burk RD, Adrien L, Dunne A, Kawachi N, Sarta C, et al. Gene expression profiles in HPV-infected head and neck cancer. J Pathol. 2007;213(3):283–93. doi:10.1002/path.2227.

    Article  CAS  PubMed  Google Scholar 

  20. Ang KK, Sturgis EM. Human papillomavirus as a marker of the natural history and response to therapy of head and neck squamous cell carcinoma. Semin Radiat Oncol. 2012;22(2):128–42. doi:10.1016/j.semradonc.2011.12.004.

    Article  PubMed  Google Scholar 

  21. Hong AM, Dobbins TA, Lee CS, Jones D, Harnett GB, Armstrong BK, et al. Human papillomavirus predicts outcome in oropharyngeal cancer in patients treated primarily with surgery or radiation therapy. Br J Cancer. 2010;103(10):1510–7. doi:10.1038/sj.bjc.6605944.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Salazar CR, Anayannis N, Smith RV, Wang YH, Haigentz M, Garg M, et al. Combined P16 and human papillomavirus testing predicts head and neck cancer survival. Int J Cancer. 2014;135(10):2404–12. doi:10.1002/ijc.28876.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ukpo OC, Flanagan JJ, Ma XJ, Luo YL, Thorstad WL, Lewis JS. High-risk human papillomavirus E6/E7 mRNA detection by a novel in situ hybridization assay strongly correlates with p16 expression and patient outcomes in oropharyngeal squamous cell carcinoma. Am J Surg Pathol. 2011;35(9):1343–50. doi:10.1097/PAS.0b013e318220e59d.

    Article  PubMed  Google Scholar 

  24. Morshed K, Polz-Dacewicz M, Szymanski M, Polz D. Short-fragment PCR assay for highly sensitive broad-spectrum detection of human papillomaviruses in laryngeal squamous cell carcinoma and normal mucosa: clinico-pathological evaluation. Eur Arch Otorhinolaryngol. 2008;265:S89–96. doi:10.1007/s00405-007-0569-5.

    Article  PubMed  Google Scholar 

  25. Ryu CH, Ryu J, Cho KH, Moon SH, Yun T, Lee SH, et al. Human papillomavirus-related cell cycle markers can predict survival outcomes following a transoral lateral oropharyngectomy for tonsillar squamous cell carcinoma. J Surg Oncol. 2014;110(4):393–9. doi:10.1002/jso.23672.

    Article  PubMed  Google Scholar 

  26. Simonato LE, Garcia JF, Sundefeld M, Mattar NJ, Veronese LA, Miyahara GI. Detection of HPV in mouth floor squamous cell carcinoma and its correlation with clinicopathologic variables, risk factors and survival. J Oral Pathol Med. 2008;37(10):593–8. doi:10.1111/j.1600-0714.2008.00704.x.

    Article  CAS  PubMed  Google Scholar 

  27. Sugiyama M, Bhawal UK, Kawamura M, Ishioka Y, Shigeishi H, Higashikawa K, et al. Human papillomavirus-16 in oral squamous cell carcinoma: clinical correlates and 5-year survival. Br J Oral Maxillofac Surg. 2007;45(2):116–22. doi:10.1016/j.bjoms.2006.04.012.

    Article  PubMed  Google Scholar 

  28. Westra WH, Taube JM, Poeta ML, Begum S, Sidransky D, Koch WM. Inverse relationship between human papillomavirus-16 infection and disruptive p53 gene mutations in squamous cell carcinoma of the head and neck. Clin Cancer Res. 2008;14(2):366–9. doi:10.1158/1078-0432.ccr-07-1402.

    Article  CAS  PubMed  Google Scholar 

  29. Park JW, Nickel KP, Torres AD, Lee D, Lambert PF, Kimple RJ. Human papillomavirus type 16 E7 oncoprotein causes a delay in repair of DNA damage. Radiother Oncol. 2014;113(3):337–44. doi:10.1016/j.radonc.2014.08.026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Blons H, Laurent-Puig P. TP53 and head and neck neoplasms. Hum Mutat. 2003;21(3):252–7. doi:10.1002/humu.10171.

    Article  CAS  PubMed  Google Scholar 

  31. Boyle JO, Hakim J, Koch W, Vanderriet P, Hruban RH, Roa RA, et al. The incidence of p53 mutations increases with progression of head and neck-cancer. Cancer Res. 1993;53(19):4477–80.

    CAS  PubMed  Google Scholar 

  32. Cairns P, Polascik TJ, Eby Y, Tokino K, Califano J, Merlo A, et al. Frequency of homozygous deletion at P16/CDKN2 in primary human tumors. Nat Genet. 1995;11(2):210–2. doi:10.1038/ng1095-210.

    Article  CAS  PubMed  Google Scholar 

  33. Bode W, Fernandez-Catalan C, Tschesche H, Grams F, Nagase H, Maskos K. Structural properties of matrix metalloproteinases. Cell Mol Life Sci. 1999;55(4):639–52. doi:10.1007/s000180050320.

    Article  CAS  PubMed  Google Scholar 

  34. Bjorklund M, Koivunen E. Gelatinase-mediated migration and invasion of cancer cells. Biochim Et Biophys Acta-Rev Cancer. 2005;1755(1):37–69. doi:10.1016/j.bbcan.2005.03.001.

    Article  CAS  Google Scholar 

  35. Bindhu OS, Ramadas K, Sebastian P, Pillai MR. High expression levels of nuclear factor kappa B and gelatinases in the tumorigenesis of oral squamous cell carcinoma. Head Neck-J Sci Spec Head Neck. 2006;28(10):916–25. doi:10.1002/hed.20437.

    Article  CAS  Google Scholar 

  36. Chen CH, Chien CY, Huang CC, Hwang CF, Chuang HC, Fang FM, et al. Expression of FLJ10540 is correlated with aggressiveness of oral cavity squamous cell carcinoma by stimulating cell migration and invasion through increased FOXM1 and MMP-2 activity. Oncogene. 2009;28(30):2723–37. doi:10.1038/onc.2009.128.

    Article  CAS  PubMed  Google Scholar 

  37. Ruokolainen H, Paakko P, Turpeenniemi-Hujanen T. Expression of matrix metalloproteinase-9 in head and neck squamous cell carcinoma: a potential marker for prognosis. Clin Cancer Res. 2004;10(9):3110–6. doi:10.1158/1078-0432.ccr-03-0530.

    Article  CAS  PubMed  Google Scholar 

  38. Thomas GT, Lewis MP, Speight PM. Matrix metalloproteinases and oral cancer. Oral Oncol. 1999;35(3):227–33. doi:10.1016/s1368-8375(99)00004-4.

    Article  CAS  PubMed  Google Scholar 

  39. Hishikawa Y, Koji T, Dhar DK, Kinugasa S, Yamaguchi M, Nagasue N. Metallothionein expression correlates with metastatic and proliferative potential in squamous cell carcinoma of the oesophagus. Br J Cancer. 1999;81(4):712–20. doi:10.1038/sj.bjc.6690753.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Raudenska M, Gumulec J, Podlaha O, Sztalmachova M, Babula P, Eckschlager T, et al. Metallothionein polymorphisms in pathological processes. Metallomics. 2014;6(1):55–68. doi:10.1039/c3mt00132f.

    Article  CAS  PubMed  Google Scholar 

  41. Gumulec J, Raudenska M, Adam V, Kizek R, Masarik M. Metallothionein-immunohistochemical cancer biomarker: a meta-analysis. PLos One. 2014;9(1):e85346. doi:10.1371/journal.pone.0085346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cui YP, Wang JB, Zhang XY, Lang RG, Bi MX, Guo LP, et al. ECRG2, a novel candidate of tumor suppressor gene in the esophageal carcinoma, interacts directly with metallothionein 2A and links to apoptosis. Biochem Biophys Res Commun. 2003;302(4):904–15. doi:10.1016/s006-291x(03)00122-0.

    Article  CAS  PubMed  Google Scholar 

  43. Raudenska M, Sztalmachova M, Gumulec J, Fojtu M, Polanska H, Balvan J, et al. Prognostic significance of the tumour-adjacent tissue in head and neck cancers. Tumour Biol. 2015. doi:10.1007/s13277-015-3755-x.

    Google Scholar 

  44. Ostrakhovitch EA, Olsson PE, Jiang S, Cherian MG. Interaction of metallothionein with tumor suppressor p53 protein. FEBS Lett. 2006;580(5):1235–8. doi:10.1016/j.febslet.2006.01.036.

    Article  CAS  PubMed  Google Scholar 

  45. Kim HG, Kim JY, Han EH, Hwang YP, Choi JH, Park BH, et al. Metallothionein-2A overexpression increases the expression of matrix metalloproteinase-9 and invasion of breast cancer cells. FEBS Lett. 2011;585(2):421–8. doi:10.1016/j.febslet.2010.12.030.

    Article  CAS  PubMed  Google Scholar 

  46. Van Limbergen EJ, Zabrocki P, Porcu M, Hauben E, Cools J, Nuyts S. FLT1 kinase is a mediator of radioresistance and survival in head and neck squamous cell carcinoma. Acta Oncol. 2014;53(5):637–45. doi:10.3109/0284186x.2013.835493.

    Article  CAS  PubMed  Google Scholar 

  47. Wang J, Kuiatse I, Lee AV, Pan J, Giuliano A, Cui X. Sustained c-Jun-NH2-Kinase activity promotes epithelial-mesenchymal transition, invasion, and survival of breast cancer cells by regulating extracellular signal-regulated kinase activation. Mol Cancer Res. 2010;8(2):266–77. doi:10.1158/1541-7786.mcr-09-0221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Nagel R, Martens-de Kemp SR, Buijze M, Jacobs G, Braakhuis BJ, Brakenhoff RH. Treatment response of HPV-positive and HPV-negative head and neck squamous cell carcinoma cell lines. Oral Oncol. 2013;49(6):560–6. doi:10.1016/j.oraloncology.2013.03.446.

    Article  PubMed  Google Scholar 

  49. Major AG, Pitty LP, Farah CS. Cancer stem cell markers in head and neck squamous cell carcinoma. Stem Cells International. 2013. Unsp 319489. doi:10.1155/2013/319489.

  50. Tsai L-L, Hu F-W, Lee S-S, Yu C-H, Yu C-C, Chang Y-C. Oct4 mediates tumor initiating properties in oral squamous cell carcinomas through the regulation of epithelial-mesenchymal transition. Plos One. 2014;9(1):e87207. doi:10.1371/journal.pone.0087207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Liu D, Zhou P, Zhang L, Wu G, Zheng Y, He F. Differential expression of Oct4 in HPV-positive and HPV-negative cervical cancer cells is not regulated by DNA methyltransferase 3A. Tumour Biol. 2011;32(5):941–50. doi:10.1007/s13277-011-0196-z.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Ministry of Health of the Czech Republic IGA MZ NT 14337-3/2013 and by Specific University Research Grants—MUNI/A/1549/2014 and MUNI/A/1326/2014 provided by the Ministry of Education, Youth and Sports of the Czech Republic in the year 2015.

Author information

Authors and Affiliations

  1. Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00, Brno, Czech Republic

    Hana Polanska, Jaromir Gumulec, Martina Raudenska, Marketa Svobodova, Jan Balvan & Michal Masarik

  2. Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, CZ-613 00, Brno, Czech Republic

    Zbynek Heger, Vojtech Adam & Rene Kizek

  3. Central European Institute of Technology, Brno University of Technology, Technicka 3058/10, CZ-616 00, Brno, Czech Republic

    Zbynek Heger, Vojtech Adam, Rene Kizek & Michal Masarik

  4. Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00, Brno, Czech Republic

    Michaela Fojtu

  5. Department of Otorhinolaryngology and Head and Neck Surgery, St. Anne’s Faculty Hospital, Pekarska 53, CZ-656 91, Brno, Czech Republic

    Hana Binkova, Zuzana Horakova & Rom Kostrica

Authors
  1. Hana Polanska
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zbynek Heger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jaromir Gumulec
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martina Raudenska
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marketa Svobodova
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jan Balvan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michaela Fojtu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hana Binkova
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zuzana Horakova
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Rom Kostrica
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Vojtech Adam
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Rene Kizek
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Michal Masarik
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michal Masarik.

Ethics declarations

Conflicts of interest

None

Electronic supplementary material

Below is the link to the electronic supplementary material.

Online resource 1

Sequences of primers used for HPV identification. (PDF 180 kb)

Online resource 2

Effect of most common high-risk HPV16 and HPV18 status on tissue gene expression. Results of statistical analysis. Displayed as a gene expression fold change (95 % confidence interval) compared to HPV-negative samples. (PDF 10 kb)

Online resource 3

Correlation between genes (co-expression pattern) in HPV-positive and HPV-negative cohort. Data shown as correlation coefficient and its corresponding p-level. (PDF 43 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Polanska, H., Heger, Z., Gumulec, J. et al. Effect of HPV on tumor expression levels of the most commonly used markers in HNSCC. Tumor Biol. 37, 7193–7201 (2016). https://doi.org/10.1007/s13277-015-4569-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-4569-6

Keywords

Search

Navigation