Skip to main content
SpringerLink
Log in

The role of osteopontin expression in melanoma progression

Tumor Biology

Cite this article

Abstract

It was shown that osteopontin (OPN), a glycophosphoprotein, plays divergent roles in cancer progression. In addition to multiple intra- and extracellular functions, it facilitates migration of tumour cells, has crucial role in cell adhesion and is associated with increased metastasis formation. In previous studies, we performed global gene expression profiling on a series of primary melanoma samples and found that OPN was significantly overexpressed in ulcerated melanomas. The major purpose of this study was to define OPN expression in primary melanomas with differing biological behaviours. OPN mRNA expression was analysed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in primary melanoma tissues. Immunohistochemistry was performed using a tissue microarray. Cox regression tests were used for survival analysis. Greater than 50 % of the tissues exhibited high protein expression that was significantly associated with tumour thickness and metastasis. OPN mRNA expression was significantly increased in thicker melanomas and lesions with an ulcerated surface. Increased expression was primarily detected in advanced-stage tumours. A multivariate Cox regression analysis revealed that high OPN expression, tumour thickness and metastasis were significantly associated with reduced relapse-free survival. In summary, high OPN mRNA and protein expression were associated with a less favourable clinical outcome of primary melanoma patients. We determined that OPN is a significant predictive factor for the survival of primary melanoma patients. Based on our and others data, the high expression of OPN may have a crucial stimulatory role in tumour progression and metastasis formation, which, thus, have been proposed as potential targets for cancer diagnosis and therapy.

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

References

  1. Forschner A, Eigentler TK, Pflugfelder A, Leiter U, Weide B, Held L, et al. Melanoma staging: facts and controversies. Clin Dermatol. 2010;28:275–80.

    Article  PubMed  Google Scholar 

  2. Godar DE (2011) Worldwide increasing incidences of cutaneous malignant melanoma. J Skin Cancer 858425

  3. Macdonald JB, Dueck AC, Gray RJ, Wasif N, Swanson DL, Sekulic A, et al. Malignant melanoma in the elderly: different regional disease and poorer prognosis. J Cancer. 2011;2:538–43.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Chin L, Garraway LA, Fisher DE. Malignant melanoma: genetics and therapeutics in the genomic era. Genes Dev. 2006;20:2149–82.

    Article  CAS  PubMed  Google Scholar 

  5. Lee B, Mukhi N, Liu D. Current management and novel agents for malignant melanoma. J Hematol Oncol. 2012;5:3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Koh A, da Silva AP, Bansal AK, Bansal M, Sun C, Lee H, et al. Role of osteopontin in neutrophil function. Immunology. 2007;122:466–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Buback F, Renkl AC, Schulz G, Weiss JM. Osteopontin and the skin: multiple emerging roles in cutaneous biology and pathology. Exp Dermatol. 2009;18:750–9.

    Article  CAS  PubMed  Google Scholar 

  8. Wai PY, Kuo PC. Osteopontin: regulation in tumor metastasis. Cancer Metastasis Rev. 2008;27:103–18.

    Article  CAS  PubMed  Google Scholar 

  9. Rittling SR, Chambers AF. Role of osteopontin in tumour progression. Br J Cancer. 2004;90:1877–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sodek J, Ganss B, McKee MD. Osteopontin. Crit Rev Oral Biol Med. 2000;11:279–303.

    Article  CAS  PubMed  Google Scholar 

  11. Wang KX, Denhardt DT. Osteopontin: role in immune regulation and stress responses. Cytokine Growth Factor Rev. 2008;19:333–45.

    Article  CAS  PubMed  Google Scholar 

  12. Hsieh YH, Juliana MM, Hicks PH, Feng G, Elmets C, Liaw L, et al. Papilloma development is delayed in osteopontin-null mice: implicating an antiapoptosis role for osteopontin. Cancer Res. 2006;66:7119–27.

    Article  CAS  PubMed  Google Scholar 

  13. Standal T, Borset M, Sundan A. Role of osteopontin in adhesion, migration, cell survival and bone remodeling. Exp Oncol. 2004;26:179–84.

    CAS  PubMed  Google Scholar 

  14. Zhou Y, Dai DL, Martinka M, Su M, Zhang Y, Campos EI, et al. Osteopontin expression correlates with melanoma invasion. J Invest Dermatol. 2005;124:1044–52.

    Article  CAS  PubMed  Google Scholar 

  15. Weber GF, Lett GS, Haubein NC. Osteopontin is a marker for cancer aggressiveness and patient survival. Br J Cancer. 2010;103:861–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. El-Tanani MK, Campbell FC, Kurisetty V, Jin D, McCann M, Rudland PS. The regulation and role of osteopontin in malignant transformation and cancer. Cytokine Growth Factor Rev. 2006;17:463–74.

    Article  CAS  PubMed  Google Scholar 

  17. Das R, Philip S, Mahabeleshwar GH, Bulbule A, Kundu GC. Osteopontin: it's role in regulation of cell motility and nuclear factor kappa b-mediated urokinase type plasminogen activator expression. IUBMB Life. 2005;57:441–7.

    Article  CAS  PubMed  Google Scholar 

  18. Packer L, Pavey S, Parker A, Stark M, Johansson P, Clarke B, et al. Osteopontin is a downstream effector of the pi3-kinase pathway in melanomas that is inversely correlated with functional PTEN. Carcinogenesis. 2006;27:1778–86.

    Article  CAS  PubMed  Google Scholar 

  19. Rangaswami H, Bulbule A, Kundu GC. Osteopontin: role in cell signaling and cancer progression. Trends Cell Biol. 2006;16:79–87.

    Article  CAS  PubMed  Google Scholar 

  20. Bellahcene A, Castronovo V, Ogbureke KU, Fisher LW, Fedarko NS. Small integrin-binding ligand n-linked glycoproteins (siblings): multifunctional proteins in cancer. Nat Rev Cancer. 2008;8:212–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Song G, Ouyang G, Bao S. The activation of akt/pkb signaling pathway and cell survival. J Cell Mol Med. 2005;9:59–71.

    Article  CAS  PubMed  Google Scholar 

  22. Shevde LA, Das S, Clark DW, Samant RS. Osteopontin: an effector and an effect of tumor metastasis. Curr Mol Med. 2010;10:71–81.

    Article  CAS  PubMed  Google Scholar 

  23. Kazanecki CC, Uzwiak DJ, Denhardt DT. Control of osteopontin signaling and function by post-translational phosphorylation and protein folding. J Cell Biochem. 2007;102:912–24.

    Article  CAS  PubMed  Google Scholar 

  24. Rangel J, Nosrati M, Torabian S, Shaikh L, Leong SP, Haqq C, et al. Osteopontin as a molecular prognostic marker for melanoma. Cancer. 2008;112:144–50.

    Article  PubMed  Google Scholar 

  25. Schultz J, Lorenz P, Ibrahim SM, Kundt G, Gross G, Kunz M. The functional -443 T/C osteopontin promoter polymorphism influences osteopontin gene expression in melanoma cells via binding of c-Myb transcription factor. Mol Carcinog. 2009;48:14–23.

    Article  CAS  PubMed  Google Scholar 

  26. Tuck AB, Chambers AF, Allan AL. Osteopontin overexpression in breast cancer: knowledge gained and possible implications for clinical management. J Cell Biochem. 2007;102:859–68.

    Article  CAS  PubMed  Google Scholar 

  27. Denhardt D. Osteopontin expression correlates with melanoma invasion. J Invest Dermatol. 2005;124:xvi–xviii.

    Article  CAS  PubMed  Google Scholar 

  28. Haqq C, Nosrati M, Sudilovsky D, Crothers J, Khodabakhsh D, Pulliam BL, et al. The gene expression signatures of melanoma progression. Proc Natl Acad Sci U S A. 2005;102:6092–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Conway C, Mitra A, Jewell R, Randerson-Moor J, Lobo S, Nsengimana J, et al. Gene expression profiling of paraffin-embedded primary melanoma using the DASL assay identifies increased osteopontin expression as predictive of reduced relapse-free survival. Clin Cancer Res Off J Am Assoc Cancer Res. 2009;15:6939–46.

    Article  CAS  Google Scholar 

  30. Rodrigues LR, Teixeira JA, Schmitt FL, Paulsson M, Lindmark-Mansson H. The role of osteopontin in tumor progression and metastasis in breast cancer. Cancer Epidemiol Biomarkers Prev. 2007;16:1087–97.

    Article  CAS  PubMed  Google Scholar 

  31. Smith AP, Hoek K, Becker D. Whole-genome expression profiling of the melanoma progression pathway reveals marked molecular differences between nevi/melanoma in situ and advanced-stage melanomas. Cancer Biol Ther. 2005;4:1018–29.

    Article  CAS  PubMed  Google Scholar 

  32. Jaeger J, Koczan D, Thiesen HJ, Ibrahim SM, Gross G, Spang R, et al. Gene expression signatures for tumor progression, tumor subtype, and tumor thickness in laser-microdissected melanoma tissues. Clin Cancer Res Off J Am Assoc Cancer Res. 2007;13:806–15.

    Article  CAS  Google Scholar 

  33. Mitra A, Conway C, Walker C, Cook M, Powell B, Lobo S, et al. Melanoma sentinel node biopsy and prediction models for relapse and overall survival. Br J Cancer. 2010;103:1229–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Weber GF. The metastasis gene osteopontin: a candidate target for cancer therapy. Biochim Biophys Acta. 2001;1552:61–85.

    Article  CAS  PubMed  Google Scholar 

  35. Rakosy Z, Ecsedi S, Toth R, Vizkeleti L, Hernandez-Vargas H, Lazar V, et al. Integrative genomics identifies gene signature associated with melanoma ulceration. PLoS One. 2013;8:e54958.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–8.

    Article  CAS  PubMed  Google Scholar 

  37. Koh SS, Opel ML, Wei JP, Yau K, Shah R, Gorre ME, et al. Molecular classification of melanomas and nevi using gene expression microarray signatures and formalin-fixed and paraffin-embedded tissue. Mod Pathol. 2009;22:538–46.

    Article  CAS  PubMed  Google Scholar 

  38. Lueking A, Beator J, Patz E, Mullner S, Mehes G, Amersdorfer P. Determination and validation of off-target activities of anti-CD44 variant 6 antibodies using protein biochips and tissue microarrays. Biotechniques. 2008;45:Pi–v.

    Article  PubMed  Google Scholar 

  39. Rud AK, Boye K, Oijordsbakken M, Lund-Iversen M, Halvorsen AR, Solberg SK, et al. Osteopontin is a prognostic biomarker in non-small cell lung cancer. BMC Cancer. 2013;13:540.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Cao DX, Li ZJ, Jiang XO, Lum YL, Khin E, Lee NP, et al. Osteopontin as potential biomarker and therapeutic target in gastric and liver cancers. World J Gastroenterol. 2012;18:3923–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Thoms JW, Dal Pra A, Anborgh PH, Christensen E, Fleshner N, Menard C, et al. Plasma osteopontin as a biomarker of prostate cancer aggression: relationship to risk category and treatment response. Br J Cancer. 2012;107:840–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Maier T, Laubender RP, Sturm RA, Klingenstein A, Korting HC, Ruzicka T, et al. Osteopontin expression in plasma of melanoma patients and in melanocytic tumours. J Eur Acad Dermatol Venereol. 2012;26:1084–91.

    Article  CAS  PubMed  Google Scholar 

  43. Filia A, Elliott F, Wind T, Field S, Davies J, Kukalizch K, et al. Plasma osteopontin concentrations in patients with cutaneous melanoma. Oncol Rep. 2013;30:1575–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Kluger HM, Hoyt K, Bacchiocchi A, Mayer T, Kirsch J, Kluger Y, et al. Plasma markers for identifying patients with metastatic melanoma. Clin Cancer Res Off J Am Assoc Cancer Res. 2011;17:2417–25.

    Article  CAS  Google Scholar 

  45. Raso E, Barbai T, Gyorffy B, Timar J. Prognostic and predictive markers of malignant melanoma. Magy Onkol. 2013;57:79–83.

    PubMed  Google Scholar 

  46. Atai NA, Bansal M, Lo C, Bosman J, Tigchelaar W, Bosch KS, et al. Osteopontin is up-regulated and associated with neutrophil and macrophage infiltration in glioblastoma. Immunology. 2011;132:39–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This research was supported by the Hungarian National Research Fund (OTKA K112327), the Hungarian Academy of Sciences (grant number 2011 TKI 473), TÁMOP-4.2.2/B-10/1-2010-0024 and TÁMOP-4.2.2.A-11/1/KONV-2012-0031 projects; the TÁMOP projects are cofinanced by the European Union and the European Social Fund. This research was also supported by the European Union and the State of Hungary, cofinanced by the European Social Fund in the framework of the TÁMOP-4.2.4.A/2-11/1-2012-0001 ‘National Excellence Program’. The authors have no connection with any of the companies or products mentioned in this article.

Author information

Authors and Affiliations

  1. Department of Preventive Medicine, Faculty of Public Health, University of Debrecen, Hungary, 4028, Debrecen, Kassai str. 26/b., Hungary

    Timea Kiss, Szilvia Ecsedi, Laura Vizkeleti, Viktoria Koroknai, Nora Kovács, Roza Adany & Margit Balazs

  2. MTA-DE Public Health Research Group, University of Debrecen, Debrecen, Hungary

    Timea Kiss, Szilvia Ecsedi, Laura Vizkeleti, Viktoria Koroknai, Roza Adany & Margit Balazs

  3. Department of Dermatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

    Gabriella Emri

Authors
  1. Timea Kiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Szilvia Ecsedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laura Vizkeleti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Viktoria Koroknai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gabriella Emri
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nora Kovács
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Roza Adany
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Margit Balazs
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Margit Balazs.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kiss, T., Ecsedi, S., Vizkeleti, L. et al. The role of osteopontin expression in melanoma progression. Tumor Biol. 36, 7841–7847 (2015). https://doi.org/10.1007/s13277-015-3495-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-3495-y

Keywords

search

Navigation