Clinical Oral Investigations

, Volume 22, Issue 3, pp 1477–1486 | Cite as

MAGE-A11 expression contributes to cisplatin resistance in head and neck cancer

  • Stefan Hartmann
  • Leonie Zwick
  • Mario J. J. Scheurer
  • Andreas R. Fuchs
  • Roman C. Brands
  • Axel Seher
  • Hartmut Böhm
  • Alexander C. Kübler
  • Urs D. A. Müller-Richter
Original Article



The objective of this study is to investigate the roles of melanoma-associated antigens (MAGEs) in the cisplatin treatment of head and neck cancer.

Materials and methods

We assessed the efficacy of cisplatin in a set of four head and neck cancer cell lines using a crystal violet assay. The MAGE-A expression in all cell lines was measured with RT-qPCR. The correlation between MAGE-A expression and cisplatin efficacy was investigated using Spearman’s correlation analysis. Furthermore, we established a cell line with stable overexpression of MAGE-A11 and determined influence on proliferation, cisplatin efficacy and cell apoptosis. In this cell line, the effects of cisplatin were assessed using either crystal violet assays or flow cytometry (Annexin V).


For MAGE-A11, we observed the highest correlation (r = 1.000, p = 0.0417) with low cisplatin efficacy. Stable overexpression of MAGE-A11 resulted in no changes in proliferation, but in lower cisplatin cytotoxicity and lower rates of apoptosis. Also, mouse double minute 2 homolog (MDM2) expression was induced by MAGE-A11 overexpression.


We provide evidence that MAGE-A11 expression contributes to cisplatin resistance in head and neck cancer.

Clinical relevance

Our study underscores the negative predictive role of MAGE-A11 expression in head and neck cancer.


Mage-A11 Melanoma-associated antigens Head and neck cancer Cisplatin 


Compliance with ethical standards

Conflict of interest

Stefan Hartmann declares that he has no conflict of interest. Leonie Zwick declares that she has no conflict of interest. Mario Scheurer declares that he has no conflict of interest.

Andreas Fuchs declares that he has no conflict of interest. Roman Brands declares that he has no conflict of interest. Axel Seher declares that he has no conflict of interest. Hartmut Böhm declares that he has no conflict of interest. Alexander Kübler declares that he has no conflict of interest. Urs Müller-Richter declares that he has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For this type of study, formal consent is not required

Supplementary material

784_2017_2242_MOESM1_ESM.docx (14 kb)
Supplemental 1 (DOCX 13 kb)


  1. 1.
    van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde BJ, Knuth A, Boon T (2007) A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. J Immunol 178(5):2617–2621PubMedGoogle Scholar
  2. 2.
    Old LJ, Chen YT (1998) New paths in human cancer serology. J Exp Med 187(8):1163–1167CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Kienstra MA, Neel HB, Strome SE, Roche P (2003) Identification of NY-ESO-1, MAGE-1, and MAGE-3 in head and neck squamous cell carcinoma. Head Neck 25(6):457–463. CrossRefPubMedGoogle Scholar
  4. 4.
    Muller-Richter UD, Dowejko A, Zhou W, Reichert TE, Driemel O (2008) Different expression of MAGE-A-antigens in foetal and adult keratinocyte cell lines. Oral Oncol 44(7):628–633. CrossRefPubMedGoogle Scholar
  5. 5.
    Scanlan MJ, Simpson AJ, Old LJ (2004) The cancer/testis genes: review, standardization, and commentary. Cancer Immun 4:1PubMedGoogle Scholar
  6. 6.
    Simpson AJ, Caballero OL, Jungbluth A, Chen YT, Old LJ (2005) Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer 5(8):615–625. CrossRefPubMedGoogle Scholar
  7. 7.
    Hou S, Sang M, Zhao L, Hou R, Shan B (2016) The expression of MAGE-C1 and MAGE-C2 in breast cancer and their clinical significance. Am J Surg 211(1):142–151. CrossRefPubMedGoogle Scholar
  8. 8.
    Wu J, Wang J, Shen W (2017) Identification of MAGEA12 as a prognostic outlier gene in gastric cancers. Neoplasma 64(2):238–243. CrossRefPubMedGoogle Scholar
  9. 9.
    Chen X, Wang L, Yue D, Liu J, Huang L, Yang L, Cao L, Qin G, Li A, Wang D, Wang M, Qi Y, Zhang B, van der Bruggen P, Zhang Y (2016) Correlation between the high expression levels of cancer-germline genes with clinical characteristics in esophageal squamous cell carcinoma. Histol Histopathol 32(8):793–803. doi: 10.14670/HH-11-847
  10. 10.
    Hashimoto R, Kanda M, Takami H, Shimizu D, Oya H, Hibino S, Okamura Y, Yamada S, Fujii T, Nakayama G, Sugimoto H, Koike M, Nomoto S, Fujiwara M, Kodera Y (2015) Aberrant expression of melanoma-associated antigen-D2 serves as a prognostic indicator of hepatocellular carcinoma outcome following curative hepatectomy. Oncol Lett 9(3):1201–1206. CrossRefPubMedGoogle Scholar
  11. 11.
    Zhan W, Zhang Z, Zhang Y, Ma J, Wu T, Gu Y, Li Y, Yang J (2016) Prognostic value of MAGE-A9 expression in patients with colorectal cancer. Clin Res Hepatol Gastroenterol 40(2):239–245. CrossRefPubMedGoogle Scholar
  12. 12.
    Laban S, Giebel G, Klumper N, Schrock A, Doescher J, Spagnoli G, Thierauf J, Theodoraki MN, Remark R, Gnjatic S, Krupar R, Sikora AG, Litjens G, Grabe N, Kristiansen G, Bootz F, Schuler PJ, Brunner C, Bragelmann J, Hoffmann TK, Perner S (2017) MAGE expression in head and neck squamous cell carcinoma primary tumors, lymph node metastases and respective recurrences-implications for immunotherapy. Oncotarget 8(9):14719–14735.  10.18632/oncotarget.14830 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Piotti KC, Scognamiglio T, Chiu R, Chen YT (2013) Expression of cancer/testis (CT) antigens in squamous cell carcinoma of the head and neck: evaluation as markers of squamous dysplasia. Pathol Res Pract 209(11):721–726. CrossRefPubMedGoogle Scholar
  14. 14.
    Hartmann S, Kriegebaum U, Kuchler N, Brands RC, Linz C, Kubler AC, Muller-Richter UD (2014) Correlation of MAGE-A tumor antigens and the efficacy of various chemotherapeutic agents in head and neck carcinoma cells. Clin Oral Investig 18(1):189–197. CrossRefPubMedGoogle Scholar
  15. 15.
    Brisam M, Rauthe S, Hartmann S, Linz C, Brands RC, Kubler AC, Rosenwald A, Muller-Richter UD (2016) Expression of MAGE-A1-A12 subgroups in the invasive tumor front and tumor center in oral squamous cell carcinoma. Oncol Rep 35(4):1979–1986. CrossRefPubMedGoogle Scholar
  16. 16.
    Hartmann S, Brisam M, Rauthe S, Driemel O, Brands RC, Rosenwald A, Kubler AC, Muller-Richter UD (2016) Contrary melanoma-associated antigen-a expression at the tumor front and center: a comparative analysis of stage I and IV head and neck squamous cell carcinoma. Oncol Lett 12(4):2942–2947. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ries J, Agaimy A, Vairaktaris E, Gorecki P, Neukam FW, Strassburg LH, Nkenke E (2012) Detection of MAGE-A expression predicts malignant transformation of oral leukoplakia. Cancer Investig 30(7):495–502. CrossRefGoogle Scholar
  18. 18.
    Doyle JM, Gao J, Wang J, Yang M, Potts PR (2010) MAGE-RING protein complexes comprise a family of E3 ubiquitin ligases. Mol Cell 39(6):963–974. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Yang B, O'Herrin SM, Wu J, Reagan-Shaw S, Ma Y, Bhat KM, Gravekamp C, Setaluri V, Peters N, Hoffmann FM, Peng H, Ivanov AV, Simpson AJ, Longley BJ (2007) MAGE-A, mMage-b, and MAGE-C proteins form complexes with KAP1 and suppress p53-dependent apoptosis in MAGE-positive cell lines. Cancer Res 67(20):9954–9962. CrossRefPubMedGoogle Scholar
  20. 20.
    Minges JT, Su S, Grossman G, Blackwelder AJ, Pop EA, Mohler JL, Wilson EM (2013) Melanoma antigen-A11 (MAGE-A11) enhances transcriptional activity by linking androgen receptor dimers. J Biol Chem 288(3):1939–1952. CrossRefPubMedGoogle Scholar
  21. 21.
    Nardiello T, Jungbluth AA, Mei A, Diliberto M, Huang X, Dabrowski A, Andrade VC, Wasserstrum R, Ely S, Niesvizky R, Pearse R, Coleman M, Jayabalan DS, Bhardwaj N, Old LJ, Chen-Kiang S, Cho HJ (2011) MAGE-A inhibits apoptosis in proliferating myeloma cells through repression of Bax and maintenance of survivin. Clin Cancer Res 17(13):4309–4319. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Ang KK, Chen A, Curran WJ Jr, Garden AS, Harari PM, Murphy BA, Wong SJ, Bellm LA, Schwartz M, Newman J, Adkins D, Hayes DN, Parvathaneni U, Brachman D, Ghabach B, Schneider CJ, Greenberg M, Anne PR (2012) Head and neck carcinoma in the United States: first comprehensive report of the longitudinal oncology registry of head and neck carcinoma (LORHAN). Cancer 118(23):5783–5792. CrossRefPubMedGoogle Scholar
  23. 23.
    Skvortsov S, Dudas J, Eichberger P, Witsch-Baumgartner M, Loeffler-Ragg J, Pritz C, Schartinger VH, Maier H, Hall J, Debbage P, Riechelmann H, Lukas P, Skvortsova I, Group EP (2014) Rac1 as a potential therapeutic target for chemo-radioresistant head and neck squamous cell carcinomas (HNSCC). Br J Cancer 110(11):2677–2687. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Ries J, Schultze-Mosgau S, Neukam F, Diebel E, Wiltfang J (2005) Investigation of the expression of melanoma antigen-encoding genes (MAGE-A1 to -A6) in oral squamous cell carcinomas to determine potential targets for gene-based cancer immunotherapy. Int J Oncol 26(3):817–824PubMedGoogle Scholar
  25. 25.
    Ries J, Vairaktaris E, Mollaoglu N, Wiltfang J, Neukam FW, Nkenke E (2008) Expression of melanoma-associated antigens in oral squamous cell carcinoma. J Oral Pathol Med 37(2):88–93. CrossRefPubMedGoogle Scholar
  26. 26.
    Muller-Richter UD, Dowejko A, Peters S, Rauthe S, Reuther T, Gattenlohner S, Reichert TE, Driemel O, Kubler AC (2010) MAGE-A antigens in patients with primary oral squamous cell carcinoma. Clin Oral Investig 14(3):291–296. CrossRefPubMedGoogle Scholar
  27. 27.
    Cuffel C, Rivals JP, Zaugg Y, Salvi S, Seelentag W, Speiser DE, Lienard D, Monnier P, Romero P, Bron L, Rimoldi D (2011) Pattern and clinical significance of cancer-testis gene expression in head and neck squamous cell carcinoma. Int J Cancer 128(11):2625–2634. CrossRefPubMedGoogle Scholar
  28. 28.
    Ries J, Agaimy A, Vairaktaris E, Kwon Y, Neukam FW, Strassburg LH, Nkenke E (2012) Evaluation of MAGE-A expression and grade of dysplasia for predicting malignant progression of oral leukoplakia. Int J Oncol 41(3):1085–1093. CrossRefPubMedGoogle Scholar
  29. 29.
    Hartmann S, Kriegebaum U, Kuchler N, Lessner G, Brands RC, Linz C, Schneider T, Kubler AC, Muller-Richter UD (2013) Efficacy of cetuximab and panitumumab in oral squamous cell carcinoma cell lines: prognostic value of MAGE-A subgroups for treatment success. J Craniomaxillofac Surg 41(7):623–629. CrossRefPubMedGoogle Scholar
  30. 30.
    Sang M, Gu L, Liu F, Lian Y, Yin D, Fan X, Ding C, Huang W, Liu S, Shan B (2016) Prognostic significance of MAGE-A11 in esophageal squamous cell carcinoma and identification of related genes based on DNA microarray. Arch Med Res 47(3):151–161. CrossRefPubMedGoogle Scholar
  31. 31.
    Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O, Castedo M, Kroemer G (2012) Molecular mechanisms of cisplatin resistance. Oncogene 31(15):1869–1883. CrossRefPubMedGoogle Scholar
  32. 32.
    Momand J, Zambetti GP, Olson DC, George D, Levine AJ (1992) The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69(7):1237–1245CrossRefPubMedGoogle Scholar
  33. 33.
    Hientz K, Mohr A, Bhakta-Guha D, Efferth T (2017) The role of p53 in cancer drug resistance and targeted chemotherapy. Oncotarget 8(5):8921–8946.  10.18632/oncotarget.13475 CrossRefPubMedGoogle Scholar
  34. 34.
    Marcar L, Ihrig B, Hourihan J, Bray SE, Quinlan PR, Jordan LB, Thompson AM, Hupp TR, Meek DW (2015) MAGE-A cancer/testis antigens inhibit MDM2 Ubiquitylation function and promote increased levels of MDM4. PLoS One 10(5):e0127713. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Iglesias Docampo LC, Haddad R, Rordorf T, Kiyota N, Tahara M, Monga M, Lynch M, Geese WJ, Kopit J, Shaw JW, Gillison ML (2016) Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 375(19):1856–1867. CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Zhang J, Sang M, Gu L, Liu F, Li W, Yin D, Wu Y, Liu S, Huang W, Shan B (2017) Zebularine treatment induces MAGE-A11 expression and improves CTL cytotoxicity using a novel identified HLA-A2-restricted MAGE-A11 peptide. J Immunother 40(6):211–220. doi:

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Stefan Hartmann
    • 1
    • 2
  • Leonie Zwick
    • 1
  • Mario J. J. Scheurer
    • 1
  • Andreas R. Fuchs
    • 1
  • Roman C. Brands
    • 1
    • 3
  • Axel Seher
    • 1
  • Hartmut Böhm
    • 1
  • Alexander C. Kübler
    • 1
  • Urs D. A. Müller-Richter
    • 1
  1. 1.Department of Oral and Maxillofacial Plastic SurgeryUniversity Hospital WürzburgWürzburgGermany
  2. 2.Interdisciplinary Center for Clinical ResearchUniversity Hospital WürzburgWürzburgGermany
  3. 3.Comprehensive Cancer Center MainfrankenUniversity Hospital WürzburgWürzburgGermany

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