Skip to main content

Advertisement

SpringerLink
Log in

Zinc finger A20 and NF-κB correlate with high-risk human papillomavirus of squamous cell carcinoma patients

  • Research Article
  • Published:
Tumor Biology

Abstract

Genital human papillomavirus (HPV) is associated with the development of cutaneous malignant tumors, and differences in HPV subtypes are found in several cancers by histology. NF-κB is persistently activated in most cancers and confers a survival advantage to cancer cells, while A20 is a critical negative regulator of NF-κB and is an important tumor suppressor inactivated in B cell lymphomas. This study was undertaken to identify HPV types in cutaneous squamous cell carcinoma (SCC) as well as to determine whether the crosstalk of A20/NF-κB was involved in HPV-induced SCC. Overall, HPV positivity was observed to be 66.2 %, with HPV16 being most common followed by infection with HPV18. Out of 43 HPV-positive samples, 35 samples were positive for one or more high-risk HPV (HR-HPV) types, suggesting a high association of SCC with HR-HPV infection, while only five HPV infections were detected in 21 normal skin samples and low-risk HPV (LR-HPV) infection was the most common. Both A20 and NF-κB were overexpressed in HPV-positive SCC samples (56 vs 87.4 %) and were closely correlated with TNM stage and lymph node transfer, respectively. More interestingly, the expression of A20 and NF-κB was much higher in HR-HPV samples than in LR-HPV samples. These results suggest that the crosstalk of A20 and NF-κB may contribute to HR-HPV-associated tumor growth and metastasis of SCC and may be a novel therapeutic target for SCC in the future.

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
Fig. 3

Similar content being viewed by others

References

  1. Brantsch KD, Meisner C, Schönfisch B, Trilling B, Wehner-Caroli J, Rocken M, et al. Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study. Lancet Oncol. 2008;9(8):713–20.

    Article  Google Scholar 

  2. Peng H, He Q, Zhu J, Peng C. Effect of GSTM1 polymorphism on risks of basal cell carcinoma and squamous cell carcinoma: a meta-analysis. Tumor Biol. 2013;34(2):675–81.

    Article  CAS  Google Scholar 

  3. Arron ST, Jennings L, Nindl I, Rosl F, Bouwes Bavinck JN, Seckin D, et al. Viral oncogenesis and its role in nonmelanoma skin cancer. Br J Dermatol. 2011;164(6):1201–13.

    Article  Google Scholar 

  4. Zang W, Wang Y, Du Y, Xuan X, Wang T, Li M, et al. Differential expression profiling of microRNA and their potential involvement in esophageal squamous cell carcinoma. Tumor Biol. 2014;35(4):3295–304.

    Article  CAS  Google Scholar 

  5. Boulet G, Horvath C, Broeck DV, Sahebali S, Bogers J. Human papillomavirus: E6 and E7 oncogenes. Int J Biochem Cell Biol. 2007;39(11):2006–11.

    Article  CAS  Google Scholar 

  6. Sun SC, Cesarman E. NF-κB as a target for oncogenic viruses. Curr Top Microbiol Immunol. 2011;349(2):197–244.

    CAS  PubMed  Google Scholar 

  7. James MA, Lee JH, Klingelhutz AJ. Human papillomavirus type 15 E6 activates NF-kappaB, induces cIAP-2 expression, and protects against apoptosis in a PDZ binding motif-dependent manner. J Virol. 2006;80(11):5301–7.

    Article  CAS  Google Scholar 

  8. Pim D, Bergant M, Boon SS, Ganti K, et al. Human papillomaviruses and the specificity of PDZ domain targeting. FEBS J. 2012;279(19):3530–7.

    Article  CAS  Google Scholar 

  9. Spitkovsky D, Hehner SP, Hofmann TG, Mlller A, Schmitz ML. The human papillomavirus oncoprotein E7 attenuates NF-kappa B activation by targeting the Ikappa B kinase complex. J Biol Chem. 2002;277(28):25576–82.

    Article  CAS  Google Scholar 

  10. Opipari AW, Boguski MS, Dixit V. The A20 cDNA induced by tumor necrosis factor alpha encodes a novel type of zinc finger protein. J Biol Chem. 1990;265(25):14705–8.

    Article  CAS  Google Scholar 

  11. Beyaert R, Heyninck K, Van Huffel S. A20 and A20-binding proteins as cellular inhibitors of nuclear factor-kappa B-dependent gene expression and apoptosis. Biochem Pharmacol. 2000;60(8):1143–51.

    Article  CAS  Google Scholar 

  12. Zhang B, Guan CC, Chen WT, Zhang P, Yan M, Shi JH, et al. A20 inhibits human salivary adenoid cystic carcinoma cells invasion via blocking nuclear factor-kappaB activation. Chin Med J (Engl). 2007;120(20):1830–5.

    Article  CAS  Google Scholar 

  13. Zhou XD, Yu JP, Liu J, Luo HS, Chen HX, Yu HG. Overexpression of cellular FLICE-inhibitory protein (FLIP) in gastric adenocarcinoma. Clin Sci (Lond). 2004;106(4):397–405.

    Article  CAS  Google Scholar 

  14. Massi D, Tarantini F, Franchi A, Paglierani M, Di Serio C, Pellerito S, et al. Evidence for differential expression of Notch receptors and their ligands in melanocytic nevi and cutaneous malignant melanoma. Mod Pathol. 2006;19(2):246–54.

    Article  CAS  Google Scholar 

  15. Aldabagh B, Angeles JG, Cardones AR, Arron ST. Cutaneous squamous cell carcinoma and human papillomavirus: is there an association? Dermatol Surg. 2013;39(1Pt1):1–23.

    Article  CAS  Google Scholar 

  16. Burk RD, Kadish AS. Treasure hunt for human papillomaviruses in nonmelanoma skin cancers. J Natl Cancer Inst. 1996;88(12):781–2.

    Article  CAS  Google Scholar 

  17. Dang C, Koehler A, Forschner T, Sehr P, Michael K, Pawlita M, et al. E6/E7 expression of human papillomavirus types in cutaneous squamous cell dysplasia and carcinoma in immunosuppressed organ transplant recipients. Br J Dermatol. 2006;155(1):129–36.

    Article  CAS  Google Scholar 

  18. Baeuerle PA, Baltimore D. NF-kappa B: ten years after. Cell. 1996;87(1):13–20.

    Article  CAS  Google Scholar 

  19. Chen Z, Yan B, van Waes C. The role of the NF-kappaB transcriptome and proteome as biomarkers in human head and neck squamous cell carcinoma. Biomark Med. 2008;2(4):409–26.

    Article  CAS  Google Scholar 

  20. Fontaine V, van der Meijden E, de Graaf J, ter Schegget J, Struyk L. A functional NF-kappaB binding site in the human papillomavirus type 16 long control region. Virology. 2000;272(1):40–9.

    Article  CAS  Google Scholar 

  21. Opipari Jr AW, Hu HM, Yabkowitz R, Dixit VM. The A20 zinc finger protein protects cells from tumor necrosis factor cytotoxicity. J Biol Chem. 1992;267(18):12424–7.

    Article  CAS  Google Scholar 

  22. Boone DL, Turer EE, Lee EG, Ahmad RC, Wheeler MT, Tsui C, et al. The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol. 2004;5(10):1052–60.

    Article  CAS  Google Scholar 

  23. Kowalczuk O, Burzykowski T, Niklinska WE, Kozlowski M, Chyczewski L, Niklinski J, et al. Tumor Biol. 2014;35(5):4619–28.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Youth Foundation of Natural Science Foundation Project of Jiangsu Province (No. BK2012153).

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Department of Dermatology, The Third Affiliated Hospital of Suzhou University, 185 Juqian Street, Changzhou, Jiangsu, People’s Republic of China

    Ya-Juan Tang, Xiao-Ming Liu, Chun-Xing Xu, Sai Cheng & Ru-Zhi Zhang

  2. Division of Dermatology, Department of Medicine, Mosul Medical College, University of Mosul, Mosul, Iraq

    Ahmad Taha Khalaf

  3. Department of Pathology, The Third Affiliated Hospital of Suzhou University, Changzhou, Jiangsu, People’s Republic of China

    Wei Zhao

Authors
  1. Ya-Juan Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ahmad Taha Khalaf
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiao-Ming Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chun-Xing Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wei Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sai Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ru-Zhi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiao-Ming Liu.

Additional information

Ya-Juan Tang and Ahmad Taha Khalaf contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tang, YJ., Khalaf, A.T., Liu, XM. et al. Zinc finger A20 and NF-κB correlate with high-risk human papillomavirus of squamous cell carcinoma patients. Tumor Biol. 35, 11855–11860 (2014). https://doi.org/10.1007/s13277-014-2416-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-014-2416-9

Keywords

Search

Navigation