Tumor Biology

, Volume 36, Issue 12, pp 9789–9794 | Cite as

The clinical and prognostic significance of midkine in breast cancer patients

Research Article

Abstract

Midkine overexpression has been shown to be a tumor biomarker in several types of human cancer, but little is known about the clinical significance of midkine in breast cancer patients. The aim of this study was to analyze the expression of midkine in breast cancer and its correlation with clinicopathological characteristics, including breast cancer patient’s survival. The expression status of midkine in breast cancer from Gene Expression Omnibus (GEO accession number: GDS3853) was observed initially. Furthermore, the expression of midkine messenger RNA (mRNA) and protein was examined in breast cancer and normal mammary tissues through real-time PCR and immunohistochemistry. Moreover, the relationship of midkine protein expression with clinical characteristics of 170 breast cancer patients was analyzed by immunohistochemistry. In our results, midkine was up-expressed in breast cancer tissues compared with normal mammary tissues in microarray data (GDS3853). Midkine mRNA and protein expression was significantly increased in breast cancer tissues than in normal mammary tissues. By immunohistochemistry, high levels of midkine protein were positively associated with the status of clinical stage, T classification, N classification, and M classification in breast cancer patients. Furthermore, midkine overexpression was an independent poor prognostic indicator for the survival of patients with breast cancer. In conclusion, overexpression of midkine protein serves as an unfavorable prognostic biomarker in breast cancer patients.

Keywords

Breast cancer Midkine Prognosis Immunohistochemistry Biomarker 

Notes

Conflicts of interest

None

References

  1. 1.
    Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang XS, et al. Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet. 2015;385:977–1010.CrossRefPubMedGoogle Scholar
  2. 2.
    Lu J, Steeg PS, Price JE, Krishnamurthy S, Mani SA, Reuben J, et al. Breast cancer metastasis: challenges and opportunities. Cancer Res. 2009;69:4951–3.CrossRefPubMedGoogle Scholar
  3. 3.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.CrossRefPubMedGoogle Scholar
  4. 4.
    Bombonati A, Sgroi DC. The molecular pathology of breast cancer progression. J Pathol. 2011;223:307–17.CrossRefPubMedGoogle Scholar
  5. 5.
    Murasugi A, Tohma-Aiba Y. Production of native recombinant human midkine in the yeast, Pichia pastoris. Protein Expr Purif. 2003;27:244–52.CrossRefPubMedGoogle Scholar
  6. 6.
    Kadomatsu K, Muramatsu T. Midkine and pleiotrophin in neural development and cancer. Cancer Lett. 2004;204:127–43.CrossRefPubMedGoogle Scholar
  7. 7.
    Qi M, Ikematsu S, Maeda N, Ichihara-Tanaka K, Sakuma S, Noda M, et al. Haptotactic migration induced by midkine. Involvement of protein-tyrosine phosphatase zeta. Mitogen-activated protein kinase, and phosphatidylinositol 3-kinase. J Biol Chem. 2001;276:15868–75.CrossRefPubMedGoogle Scholar
  8. 8.
    Muramatsu T. Midkine and pleiotrophin: two related proteins involved in development, survival, inflammation and tumorigenesis. J Biochem. 2002;132:359–71.CrossRefPubMedGoogle Scholar
  9. 9.
    Choudhuri R, Zhang HT, Donnini S, Ziche M, Bicknell R. An angiogenic role for the neurokines midkine and pleiotrophin in tumorigenesis. Cancer Res. 1997;57:1814–9.PubMedGoogle Scholar
  10. 10.
    Kadomatsu K, Hagihara M, Akhter S, Fan QW, Muramatsu H, Muramatsu T. Midkine induces the transformation of NIH3T3 cells. Br J Cancer. 1997;75:354–9.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Ota K, Fujimori H, Ueda M, Shiniriki S, Kudo M, Jono H, et al. Midkine as a prognostic biomarker in oral squamous cell carcinoma. Br J Cancer. 2008;99:655–62.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Aridome K, Tsutsui J, Takao S, Kadomatsu K, Ozawa M, Aikou T, et al. Increased midkine gene expression in human gastrointestinal cancers. Jpn J Cancer Res. 1995;86:655–61.CrossRefPubMedGoogle Scholar
  13. 13.
    Ye C, Qi M, Fan QW, Ito K, Akiyama S, Kasai Y, et al. Expression of midkine in the early stage of carcinogenesis in human colorectal cancer. Br J Cancer. 1999;79:179–84.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Kato M, Shinozawa T, Kato S, Awaya A, Terada T. Increased midkine expression in hepatocellular carcinoma. Arch Pathol Lab Med. 2000;124:848–52.PubMedGoogle Scholar
  15. 15.
    Kato M, Shinozawa T, Kato S, Endo K, Terada T. Increased midkine expression in intrahepatic cholangiocarcinoma: immunohistochemical and in situ hybridization analyses. Liver. 2000;20:216–21.CrossRefPubMedGoogle Scholar
  16. 16.
    Ma Z, Li H, Wang B, Shen Q, Cui E, Min L, et al. Midkine mRNA level in peripheral blood mononuclear cells is a novel biomarker for primary non-small cell lung cancer: a prospective study. J Cancer Res Clin Oncol. 2013;139:557–62.CrossRefPubMedGoogle Scholar
  17. 17.
    Kato M, Maeta H, Kato S, Shinozawa T, Terada T. Immunohistochemical and in situ hybridization analyses of midkine expression in thyroid papillary carcinoma. Mod Pathol. 2000;13:1060–5.CrossRefPubMedGoogle Scholar
  18. 18.
    Hidaka H, Yagasaki H, Takahashi Y, Hama A, Nishio N, Tanaka M, et al. Increased midkine gene expression in childhood B-precursor acute lymphoblastic leukemia. Leuk Res. 2007;31:1045–51.CrossRefPubMedGoogle Scholar
  19. 19.
    Moon HS, Park WI, Sung SH, Choi EA, Chung HW, Woo BH. Immunohistochemical and quantitative competitive PCR analyses of midkine and pleiotrophin expression in cervical cancer. Gynecol Oncol. 2003;88:289–97.CrossRefPubMedGoogle Scholar
  20. 20.
    Nakanishi T, Kadomatsu K, Okamoto T, Tomoda Y, Muramatsu T. Expression of midkine and pleiotropin in ovarian tumors. Obstet Gynecol. 1997;90:285–90.CrossRefPubMedGoogle Scholar
  21. 21.
    Konishi N, Nakamura M, Nakaoka S, Hiasa Y, Cho M, Uemura H, et al. Immunohistochemical analysis of midkine expression in human prostate carcinoma. Oncology. 1999;57:253–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Luo W, Li S, Peng B, Ye Y, Deng X, Yao K. Embryonic stem cells markers SOX2, OCT4 and Nanog expression and their correlations with epithelial-mesenchymal transition in nasopharyngeal carcinoma. PLoS One. 2013;8, e56324.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Muramatsu T. Midkine, a heparin-binding cytokine with multiple roles in development, repair and diseases. Proce Jpn Acad Ser B Phys Biolog Sci. 2010;86:410–25.CrossRefGoogle Scholar
  24. 24.
    Ikematsu S, Yano A, Aridome K, Kikuchi M, Kumai H, Nagano H, et al. Serum midkine levels are increased in patients with various types of carcinomas. Br J Cancer. 2000;83:701–6.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Ibusuki M, Fujimori H, Yamamoto Y, Ota K, Ueda M, Shinriki S, et al. Midkine in plasma as a novel breast cancer marker. Cancer Sci. 2009;100:1735–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Kretschmer C, Sterner-Kock A, Siedentopf F, Schoenegg W, Schlag PM, Kemmner W. Identification of early molecular markers for breast cancer. Mol Cancer. 2011;10:15.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Qin Li L, Huang HL, Ping JL, Xu W, Li J, Dai LC. Expression of midkine and endoglin in breast carcinomas with different immunohistochemical profiles. APMIS. 2011;119:103–10.CrossRefPubMedGoogle Scholar
  28. 28.
    Shimada H, Nabeya Y, Tagawa M, Okazumi S, Matsubara H, Kadomatsu K, et al. Preoperative serum midkine concentration is a prognostic marker for esophageal squamous cell carcinoma. Cancer Sci. 2003;94:628–32.CrossRefPubMedGoogle Scholar
  29. 29.
    Zhu WW, Guo JJ, Guo L, Jia HL, Zhu M, Zhang JB, et al. Evaluation of midkine as a diagnostic serum biomarker in hepatocellular carcinoma. Clin Cancer Res. 2013;19:3944–54.CrossRefPubMedGoogle Scholar
  30. 30.
    Ota K, Fujimori H, Ueda M, Jono H, Shinriki S, Ota T, et al. Midkine expression is correlated with an adverse prognosis and is down-regulated by p53 in oral squamous cell carcinoma. Int J Oncol. 2010;37:797–804.PubMedGoogle Scholar
  31. 31.
    Zhao ZQ, Yang S, Lu HS. Expression of midkine and vascular endothelial growth factor in gastric cancer and the association of high levels with poor prognosis and survival. Mol Med Rep. 2012;5:415–9.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Fuguang Li
    • 1
  • Peijun Tian
    • 2
  • Jun Zhang
    • 1
  • Changyuan Kou
    • 3
  1. 1.Department of General SurgeryThe Central Hospital of Ankang CityAnkangChina
  2. 2.Department of HematologyThe Central Hospital of Ankang CityAnkangChina
  3. 3.Department of OncologyThe Central Hospital of Ankang CityAnkangChina

Personalised recommendations