Skip to main content

Advertisement

SpringerLink
Log in

Expression of Kallikrein-Related Peptidase 6 in Primary Mucosal Malignant Melanoma of the Head and Neck

  • Original Paper
  • Published:
Head and Neck Pathology Aims and scope Submit manuscript

Abstract

Mucosal melanomas of the head and neck (MMHN) are aggressive tumors with poor prognosis, different opposed to cutaneous melanoma. In this study, we characterized primary mucosal malignant melanoma for the expression of Kallikrein-related peptidase 6 (KLK6), a member of the KLK family with relevance to the malignant phenotype in various cancer types including cutaneous melanoma. Paraffin-embedded MMHN of 22 patients were stained immunohistochemically for KLK6 and results were correlated with clinical and pathological data. In 77.3% (17/22) of MMHN cases, positive KLK6 staining was found. Staining pattern for tumor cells showed a predominant cytoplasmic staining. However, in six cases we also observed a prominent nuclear staining. MMHN with a high KLK6 expression showed significantly better outcome concerning local recurrence-free survival (p = 0.013) and nuclear KLK6 staining was significantly associated with the survival status (p = 0.027). Overexpression of KLK6 was detected in more than 70% of MMHN and approximately 40% of tumors showed a strong expression pattern. Correlation between clinical outcome of MMHN patients and overexpression of KLK6 has not been addressed so far. Our data demonstrate for the first time increased levels of KLK6 in MMHN and strengthen the hypothesis that there might be a context-specific regulation and function of KLK6 in mucosal melanoma.

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. Mihajlovic M, Vlajkovic S, Jovanovic P, Stefanovic V. Primary mucosal melanomas: a comprehensive review. Int J Clin Exp Pathol. 2012;5:739–53.

    PubMed  PubMed Central  Google Scholar 

  2. Prasad ML, et al. Expression and significance of cancer testis antigens in primary mucosal melanoma of the head and neck. Head Neck. 2004;26:1053–7.

    Article  PubMed  Google Scholar 

  3. Holmstrom M, Lund VJ. Malignant melanomas of the nasal cavity after occupational exposure to formaldehyde. Br J Ind Med. 1991;48:9–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Dahlgren L, Schedvins K, Kanter-Lewensohn L, Dalianis T, Ragnarsson-Olding BK. Human papilloma virus (HPV) is rarely detected in malignant melanomas of sun sheltered mucosal membranes. Acta Oncol. 2005;44:694–9.

    Article  PubMed  Google Scholar 

  5. Lundberg R, et al. Human herpes virus DNA is rarely detected in non-UV light-associated primary malignant melanomas of mucous membranes. Anticancer Res. 2006;26:3627–31.

    CAS  PubMed  Google Scholar 

  6. Thierauf J, et al. Mucosal melanoma of the head and neck. Laryngorhinootologie. 2015;94:812–8.

    Article  CAS  PubMed  Google Scholar 

  7. Liao JJ, et al. Fast neutron radiotherapy for primary mucosal melanomas of the head and neck. Head Neck. 2013. doi:10.1002/hed.23428.

    Google Scholar 

  8. Zenda S, et al. Proton beam therapy as a nonsurgical approach to mucosal melanoma of the head and neck: a pilot study. Int J Radiat Oncol Biol Phys. 2011;81:135–9.

    Article  PubMed  Google Scholar 

  9. Yi JH, et al. Dacarbazine-based chemotherapy as first-line treatment in noncutaneous metastatic melanoma: multicenter, retrospective analysis in Asia. Melanoma Res. 2011;21:223–7.

    Article  CAS  PubMed  Google Scholar 

  10. Hodi FS, et al. Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol. 2008;26:2046–51.

    Article  CAS  PubMed  Google Scholar 

  11. Minor DR, et al. Sunitinib therapy for melanoma patients with KIT mutations. Clin Cancer Res. 2012;18:1457–63.

    Article  CAS  PubMed  Google Scholar 

  12. Lourenço SV, et al. Head and neck mucosal melanoma: a review. Am J Dermatopathol. 2014. doi:10.1097/DAD.0000000000000035.

    Google Scholar 

  13. Thierauf J, et al. Identification and clinical relevance of PD-L1 expression in primary mucosal malignant melanoma of the head and neck. Melanoma Res. 2015. doi:10.1097/CMR.0000000000000197.

    PubMed  Google Scholar 

  14. Paliouras M, Borgono C, Diamandis EP. Human tissue kallikreins: the cancer biomarker family. Cancer Lett. 2007;249:61–79.

    Article  CAS  PubMed  Google Scholar 

  15. Yousef GM, et al. Human tissue kallikreins: from gene structure to function and clinical applications. Adv Clin Chem. 2005;39:11–79.

    Article  PubMed  Google Scholar 

  16. Prassas I, Eissa A, Poda G, Diamandis EP. Unleashing the therapeutic potential of human kallikrein-related serine proteases. Nat Rev Drug Discov. 2015;14:183–202.

    Article  CAS  PubMed  Google Scholar 

  17. Bayani J, Diamandis EP. The physiology and pathobiology of human kallikrein-related peptidase 6 (KLK6). Clin Chem Lab Med. 2012;50:211–33.

    Article  CAS  Google Scholar 

  18. Krenzer S, et al. Expression and function of the kallikrein-related peptidase 6 in the human melanoma microenvironment. J Investig Dermatol. 2011;131:2281–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Oikonomopoulou K, Diamandis EP, Hollenberg MD. Kallikrein-related peptidases: proteolysis and signaling in cancer, the new frontier. Biol Chem. 2010;391:299–310.

    CAS  PubMed  Google Scholar 

  20. Drucker KL, et al. Clinical significance and novel mechanism of action of kallikrein 6 in glioblastoma. Neuro Oncol. 2013;15:305–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pampalakis G, et al. A tumor-protective role for human kallikrein-related peptidase 6 in breast cancer mediated by inhibition of epithelial-to-mesenchymal transition. Cancer Res. 2009;69:3779–87.

    Article  CAS  PubMed  Google Scholar 

  22. Schrader CH, et al. Kallikrein-related peptidase 6 regulates epithelial-to-mesenchymal transition and serves as prognostic biomarker for head and neck squamous cell carcinoma patients. Mol Cancer. 2015;14:107.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Paliouras M, Diamandis EP. Androgens act synergistically to enhance estrogen-induced upregulation of human tissue kallikreins 10, 11, and 14 in breast cancer cells via a membrane bound androgen receptor. Mol Oncol. 2008;1:413–24.

    Article  PubMed  Google Scholar 

  24. Breitenbach U, et al. Keratinocyte-specific onset of serine protease BSSP expression in experimental carcinogenesis. J Investig Dermatol. 2001;117:634–40.

    Article  CAS  PubMed  Google Scholar 

  25. Ignatenko NA, et al. The chemopreventive agent alpha-difluoromethylornithine blocks Ki-ras-dependent tumor formation and specific gene expression in Caco-2 cells. Mol Carcinog. 2004;39:221–33.

    Article  CAS  PubMed  Google Scholar 

  26. Kuzmanov U, et al. Separation of kallikrein 6 glycoprotein subpopulations in biological fluids by anion-exchange chromatography coupled to ELISA and identification by mass spectrometry. Proteomics. 2012;12:799–809.

    Article  CAS  PubMed  Google Scholar 

  27. Chow TF, et al. Kallikreins as microRNA targets: an in silico and experimental-based analysis. Biol Chem. 2008;389:731–8.

    Article  CAS  PubMed  Google Scholar 

  28. Klucky B, et al. Kallikrein 6 induces E-cadherin shedding and promotes cell proliferation, migration, and invasion. Cancer Res. 2007;67:8198–206.

    Article  CAS  PubMed  Google Scholar 

  29. van Diest PJ, et al. A scoring system for immunohistochemical staining: consensus report of the task force for basic research of the EORTC-GCCG. European Organization for Research and Treatment of Cancer-Gynaecological Cancer Cooperative Group. J Clin Pathol. 1997;50:801–4.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Qureshi A, Pervez S. Allred scoring for ER reporting and it’s impact in clearly distinguishing ER negative from ER positive breast cancers. J Pak Med Assoc. 2010;60:350–3.

    PubMed  Google Scholar 

  31. Anisowicz A, Sotiropoulou G, Stenman G, Mok SC, Sager R. A novel protease homolog differentially expressed in breast and ovarian cancer. Mol Med. 1996;2:624–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Seiz L, et al. Stromal cell-associated expression of kallikrein-related peptidase 6 (KLK6) indicates poor prognosis of ovarian cancer patients. Biol Chem. 2012;393:391–401.

    Article  CAS  PubMed  Google Scholar 

  33. Gabril M, et al. Immunohistochemical analysis of kallikrein-related peptidases in the normal kidney and renal tumors: potential clinical implications. Biol Chem. 2010;391:403–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

    Authors and Affiliations

    1. Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center Ulm, Ulm, Germany

      Julia Thierauf, Johannes A. Veit, Johannes Döscher & Thomas K. Hoffmann

    2. Section Experimental and Translational Head and Neck Oncology, Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center Heidelberg, Heidelberg, Germany

      Annette Affolter, Jennifer Grünow, Peter K. Plinkert & Jochen Hess

    3. Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany

      Jochen Hess

    4. Institute of Pathology, University Medical Center Ulm, Ulm, Germany

      Jochen K. Lennerz, Stephanie E. Weissinger & Lisa Grünmüller

    5. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA

      Jochen K. Lennerz

    6. Institute of Pathology, University Medical Center Heidelberg, Heidelberg, Germany

      Annette Affolter

    7. Department of Dermatology and Venerology, University Medical Center of Cologne, Cologne, Germany

      Cornelia Mauch

    8. Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center Essen, Essen, Germany

      Christoph Bergmann

    9. Department of Otolaryngology, Head and Neck Surgery, Technical University Hospital Munich, Munich, Germany

      Andreas Knopf

    Authors
    1. Julia Thierauf
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Johannes A. Veit
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Jochen K. Lennerz
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Stephanie E. Weissinger
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Annette Affolter
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Johannes Döscher
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Christoph Bergmann
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Andreas Knopf
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Jennifer Grünow
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Lisa Grünmüller
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Cornelia Mauch
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Peter K. Plinkert
      View author publications

      You can also search for this author in PubMed Google Scholar

    13. Thomas K. Hoffmann
      View author publications

      You can also search for this author in PubMed Google Scholar

    14. Jochen Hess
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Julia Thierauf.

    Additional information

    Thomas K. Hoffmann and Jochen Hess have contributed equally to the research project.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Thierauf, J., Veit, J.A., Lennerz, J.K. et al. Expression of Kallikrein-Related Peptidase 6 in Primary Mucosal Malignant Melanoma of the Head and Neck. Head and Neck Pathol 11, 314–320 (2017). https://doi.org/10.1007/s12105-016-0769-7

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12105-016-0769-7

    Keywords

    Search

    Navigation