Tumor Biology

, Volume 37, Issue 5, pp 6953–6962 | Cite as

Assessment of changes in expression and presentation of NKG2D under influence of MICA serum factor in different stages of breast cancer

  • R. Roshani
  • M. Ghafourian Boroujerdnia
  • A. H. Talaiezadeh
  • A. Khodadadi
Original Article

Abstract

Breast cancer is the most common cancer in women worldwide. In this study, we correlated the serum level of major histocompatibility complex class I-related chain A (sMICA) with expression and presentation of NKG2D receptors on NK cells among patients with breast cancer. Peripheral blood (PB) samples were collected from 49 healthy and 49 breast cancer patients before surgery and chemotherapy. The expression and presentation of NKG2D were assessed using qRT-PCR and flow cytometry, respectively. Furthermore, sMICA levels were determined using ELISA. In flow cytometry, whole blood samples were stained with anti-CD56/NKG2D/CD3 and the obtained results were analyzed using WinMDI software. In addition, SPSS software was used for statistical analysis of data. Significantly higher levels sMICA were detected in the sera of the majority of cancer patients in contrast to healthy volunteers (P < 0.001). The expression and presentation of NKG2D receptor were significantly lower than those in healthy persons, and with an inverse correlation to sMICA and positively correlated with tumor stage. Our study showed that sMICA may have an important role in diminishing the expression and presentation of NKG2D receptor in breast cancer patients and proposes the notion that sMICA can be a target candidate for treatment of breast cancer.

Keywords

Breast cancer NKG2D sMICA Flow cytometry qRT-PCR 

Abbreviations

MIC

Major histocompatibility complex class I chain-related protein

qRT-PCR

Quantitative real-time PCR

CT

Threshold cycle

FITC

Fluorescein isothiocyanate

PE

Phycoerythrine

KIR

Killer immunoglobulin-like receptors

ELISA

Enzyme-linked immunosorbent assay

Notes

Acknowledgments

This study is part of the MSc thesis of Reyhaneh Roshani. Specific thanks to Vice Chancellor of Research, Ahvaz Jundishapur University of Medical Sciences, for the financial support, and the authors are grateful to breast cancer patients and normal volunteers for helping in this project.

References

  1. 1.
    Agarwal G, Ramakant P, Ernesto R, Forgach S, Carrasco Rendon J, Chaparro JA, et al. Breast cancer care in developing countries. World J Surg. 2009;33:2069–76.CrossRefPubMedGoogle Scholar
  2. 2.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics. CA Cancer J Clin. 2008;58(2):71–96.CrossRefPubMedGoogle Scholar
  3. 3.
    Harirchi I, Karbakhsh M, Montazeri A, Ebrahimi M, Jarvandi S, Zamani N, et al. Decreasing trend of tumour size and downstaging in breast cancer in Iran: results of a 15-year study. Eur J Cancer Prev. 2010;19:126–30.CrossRefPubMedGoogle Scholar
  4. 4.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM, et al. Cancer incidence and mortality worldwide, IARC CancerBase No. 10. Lyon: IARC; 2010.Google Scholar
  5. 5.
    Goya M. Iranian annual cancer registration report 2005/2006. Tehran: Ministry of Health and Medical Education, Health Deputy, Center for Disease Control and Prevention; 2007. In Persian.Google Scholar
  6. 6.
    Chong PN, Krishnan M, Hong CY, Swah TS. Knowledge and practice of breast cancer screening amongst public health nurses in Singapore. Singapore Med J. 2002;43(10):509–16.PubMedGoogle Scholar
  7. 7.
    Ko CM, Sadler GR, Ryujin L, Dong A. Filipina American women’s breast cancer knowledge, attitudes, and screening behaviors. BMC Public Health. 2003;3:27.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Arreygue-Garcia NA, Daneri-Navarro A, del Toro-Arreola A, Cid-Arregui A, Gonzalez-Ramella O, Jave-Suarez LF, et al. Augmented serum level of major histocompatibility complex class I-related chain A (MICA) protein and reduced NKG2D expression on NK and T cells in patients with cervical cancer and precursor lesions. BMC Cancer. 2008;8:16.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol. 2008;9(5):503–10.CrossRefPubMedGoogle Scholar
  10. 10.
    Konjevic G, Mirjacic Martinovic K, Vuletic A, Jovic V, Jurisic V, Babovic N, et al. Low expression of CD161 and NKG2D activating NK receptor is associated with impaired NK cell cytotoxicity in metastatic melanoma patients. Clin Exp Metastasis. 2007;24(1):1–11.CrossRefPubMedGoogle Scholar
  11. 11.
    Robertson MJ, Ritz J. Biology and clinical relevance of human natural killer cells. Blood. 1990;76(12):2421–38.PubMedGoogle Scholar
  12. 12.
    Trinchieri G. Biology of natural killer cells. Adv Immunol. 1989;47:187–376.CrossRefPubMedGoogle Scholar
  13. 13.
    Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science. 1999;285:727–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Groh V, Rhinehart R, Randolph-Habecker J, Topp MS, RiddellSR ST. Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nat Immunol. 2001;2:255–60.CrossRefPubMedGoogle Scholar
  15. 15.
    Groh V, Rhinehart R, Secrist H, Bauer S, Grabstein KH, Spies T. Broad tumour-associated expression and recognition by tumour-derived gamma delta T cells of MICA and MICB. Proc Natl Acad Sci U S A. 1999;96:6879–84.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Salih HR, Antropius H, Gieseke F, Lutz SZ, Kanz L, RammenseeHG SA. Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia. Blood. 2003;102:1389–96.CrossRefPubMedGoogle Scholar
  17. 17.
    Diefenbach A, Jensen ER, Jamieson AM, Raulet DH. Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature. 2001;413(6852):165–71.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Carbone E, Neri P, Mesuraca M, Fulciniti MT, Otsuki T, Pende D, et al. HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells. Blood. 2005;105(1):251–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Yamaguchi S, Hayashi N. Impairment of natural killer cell and dendritic cell functions by the soluble form of MHC class I-related chain A in advanced human hepatocellular carcinomas. J Hepatol. 2005;43(6):1013–20.CrossRefPubMedGoogle Scholar
  20. 20.
    Doubrovina ES, Doubrovin MM, Vider E, Sisson RB, O’Reilly RJ, Dupont B, et al. Evasion from NK cell immunity by MHC class I chain-related molecules expressing colon adenocarcinoma. J Immunol. 2003;171(12):6891–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Wu JD, Higgins LM, Steinle A, Cosman D, Haugk K, Plymate SR. Prevalent expression of the immunostimulatory MHC class I chain-related molecule is counteracted by shedding in prostate cancer. J Clin Invest. 2004;114(4):560–8.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Holdenrieder S, Stieber P, Peterfi A, Nagel D, Steinle A, Salih HR. Soluble MICA in malignant diseases. Int J Cancer. 2006;118(3):684–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Salih HR, Rammensee HG, Steinle A. Cutting edge: down-regulation of MICA on human tumours by proteolytic shedding. J Immunol. 2002;169:4098–102.CrossRefPubMedGoogle Scholar
  24. 24.
    Gregory B, Whitney G. Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res. 2014;21(4):1–6.Google Scholar
  25. 25.
    Champsaur M, Lanier LL. Effect of NKG2D ligand expression on host immune responses. Immunol Rev. 2010;235(1):267–85.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Rebecca S, Kimberly M, Ahmedin J. Cancer statistics. CA Cancer J Clin. 2015;65:5–29.CrossRefGoogle Scholar
  27. 27.
    Paul S, Ming-Ru W, Marie-Louise S, Charles S. NKG2D ligands as therapeutic targets. Cancer Immun. 2013;13(8):1–14.Google Scholar
  28. 28.
    Gang X, Xuanjun W, Jun S, Shengjun L, Xuezhong Y, Jennifer DW. Soluble NKG2D ligand promotes MDSC expansion and skews macrophage to the alternatively activated phenotype. J Hematol Oncol. 2015;8:13.CrossRefGoogle Scholar
  29. 29.
    Marten A, von Lilienfeld-Toal M, Buchler MW, Schmidt J. Soluble MIC is elevated in the serum of patients with pancreatic carcinoma diminishing γδ T cell cytotoxicity. Int J Cancer. 2006;119(10):2359–65.CrossRefPubMedGoogle Scholar
  30. 30.
    Karagoz B, Bilgi O, Kandemir EG, Sayan O, Erikci AA, Yilmaz B, et al. Decreased NKG2D expression on natural killer cells in gastric cancer patients. Inter J Hematol Oncol. 2009;19(1):0427.Google Scholar
  31. 31.
    Waldhauer I, Goehlsdorf D, Gieseke F, Weinscheenk T, Witteenbrink M, Ludwig A, et al. Tumour-associated MICA is shed by ADAM proteases. Cancer Res. 2008;68(15):6368–76. doi: 10.1158/0008-5472.CrossRefPubMedGoogle Scholar
  32. 32.
    Holdenrieder S, Stieber P, Peterfi A, Nagel D, Steinle A, Salih HR. Soluble MICB in malignant diseases: analysis of diagnostic significance and correlation with soluble MICA. Cancer Immunol Immunother. 2006;55(12):15849.CrossRefGoogle Scholar
  33. 33.
    Fabbri A, Carcangiu ML, Carbone A. Histological classification of breast cancer. Berlin: Springer; 2008. p. 2–4.Google Scholar
  34. 34.
    Gerner MY, Casey KA, Mescher MF. Defective MHC class II presentation by dendritic cells limits CD4 T cell help for antitumour CD8 T cell responses. J Immunol. 2008;181(1):155–64.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Tamaki S, Sanefuzi N, Kawakami M, Aoki K, Imai Y, Yamanaka Y, et al. Association between soluble MICA levels and disease stage IV oral squamous cell carcinoma in Japanese patients. Hum Immunol. 2008;69(2):88–93.CrossRefPubMedGoogle Scholar
  36. 36.
    McGilvray RW, Eagle RA, Watson NF, Al-Attar A, Ball G, Jafferji I, et al. NKG2D ligand expression in human colorectal cancer reveals associations with prognosis and evidence for immunoediting. Clin Cancer Res. 2009;15(22):6993–7002.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • R. Roshani
    • 1
    • 2
  • M. Ghafourian Boroujerdnia
    • 2
  • A. H. Talaiezadeh
    • 1
    • 3
  • A. Khodadadi
    • 1
    • 2
  1. 1.Cancer, Petroleum and Environmental Pollutants Research CenterAhvaz Jundishapur University of Medical SciencesAhvazIran
  2. 2.Department of Immunology, Faculty of MedicineAhvaz Jundishapur University of Medical SciencesAhvazIran
  3. 3.Department of Surgery, Faculty of MedicineAhvaz Jundishapur University of Medical SciencesAhvazIran

Personalised recommendations