Advertisement

Tumor Biology

, Volume 37, Issue 8, pp 11187–11198 | Cite as

Co-expression of ILT4/HLA-G in human non-small cell lung cancer correlates with poor prognosis and ILT4-HLA-G interaction activates ERK signaling

  • Yanwen Zhang
  • Jianqiang Zhao
  • Lijun Qiu
  • Pei Zhang
  • Juan Li
  • Dong Yang
  • Xiaojuan Wei
  • Yali Han
  • Siyue Nie
  • Yuping Sun
Original Article

Abstract

Non-small cell lung cancer (NSCLC) is the most common malignant tumor in the world, of which prognosis is generally poor due to insufficient mechanistic understanding. To explore the molecular pathogenesis of NSCLC, the co-expression of immunoglobulin-like transcript 4 (ILT4) and its ligand human leukocyte antigen G (HLA-G) in NSCLC tissues and cells were investigated. Here, we detected the expression of ILT4 and HLA-G in 81 tumor specimens from primary NSCLC patients, and we found that co-expression of ILT4/HLA-G was significantly associated with regional lymph node involvement, advanced stages, and the overall survival of patients. In NSCLC cell lines, HLA-G expression increased/decreased accordingly when ILT4 was up-/down-regulated, and ILT4 expression increased in a concentration-dependent manner via the stimulation of HLA-G fusion protein. Interestingly, HLA-G fusion protein could also up-regulate the phospho-ERK1/2 expression, which means the activation of extracellular signal-regulated kinase (ERK) signaling. All in all, our results indicate that the ILT4-HLA-G interaction might play an important role in NSCLC progression. Identification of ILT4 and HLA-G expression may provide an indicator to predict prognosis and guide prevention and treatment of NSCLC.

Keywords

Non-small cell lung cancer Immunoglobulin-like transcript 4 Human leukocyte antigen-G Extracellular signal-regulated kinase 

Abbreviations

NSCLC

Non-small cell lung cancer

ILT4

Immunoglobulin-like transcript 4

HLA-G

Human leukocyte antigen G

DC

Dendritic cells

MHCIs

Major histocompatibility complex class I molecules

ITIMs

Immunoreceptor tyrosine-based inhibitory motifs

SHP

Protein tyrosine phosphatase

VEGF-C

Vascular endothelial growth factor-C

ANGPTLs

Angiopoietin-like proteins

AKT

PI3K/protein kinase B

ERK

Extracellular signal regulated kinases

NF

Nuclear factor

OS

Overall survival

TILs

Infiltrating lymphocytes

PIRB

Paired Ig-like receptor

HSCs

Human hematopoietic stem cells

AML

Acute myeloid leukemia

EGFR

Epidermal growth factor receptor

Notes

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant No. 81372334), the Department of Science and Technology of Shandong Province (Grant No. 2013GSF12107), and the Department of Science and Technology of Jinan City (Grant No. 201201061). We thank Dong Zhao and Huiping Liu of the Department of Pathology, Jinan Central Hospital, Shandong University, for performing the immunohistochemical assays.

Author contributions

Y.S. conceived and designed the experiments. Y.Z., P.Z., J.L., D.Y., X.W., Y.H., and S.N. performed the experiments. Y.S., Y.Z., J.Z., and L.Q. analyzed data and wrote the manuscript.

Compliance with ethical standards

Conflicts of interest

None

References

  1. 1.
    Devesa SS, Bray F, Vizcaino AP, Parkin DM. International lung cancer trends by histologic type: male:female differences diminishing and adenocarcinoma rates rising. Int J Cancer. 2005;117:294–9.CrossRefPubMedGoogle Scholar
  2. 2.
    Reck M, Heigener DF, Mok T, Soria JC, Rabe KF. Management of non-small-cell lung cancer: recent developments. Lancet. 2013;382:709–19.CrossRefPubMedGoogle Scholar
  3. 3.
    Madureira P, de Mello RA, de Vasconcelos A, Zhang Y. Immunotherapy for lung cancer: for whom the bell tolls? Tumour Biol. 2015;36:1411–22.CrossRefPubMedGoogle Scholar
  4. 4.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.CrossRefPubMedGoogle Scholar
  5. 5.
    Colonna M, Nakajima H, Cella M. A family of inhibitory and activating Ig-like receptors that modulate function of lymphoid and myeloid cells. Semin Immunol. 2000;12:121–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Borges L, Cosman D. LIRs/ILTs/MIRs, inhibitory and stimulatory Ig-superfamily receptors expressed in myeloid and lymphoid cells. Cytokine Growth Factor Rev. 2000;11:209–17.CrossRefPubMedGoogle Scholar
  7. 7.
    Shiroishi M, Tsumoto K, Amano K, et al. Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G. Proc Natl Acad Sci U S A. 2003;100:8856–61.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Nakajima H, Asai A, Okada A, et al. Transcriptional regulation of ILT family receptors. J Immunol. 2003;171:6611–20.CrossRefPubMedGoogle Scholar
  9. 9.
    Sun Y, Liu J, Gao P, Wang Y, Liu C. Expression of Ig-like transcript 4 inhibitory receptor in human non-small cell lung cancer. Chest. 2008;134:783–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Liu J, Wang L, Gao W, et al. Inhibitory receptor immunoglobulin-like transcript 4 was highly expressed in primary ductal and lobular breast cancer and significantly correlated with IL-10. Diagn Pathol. 2014;9:85.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Zhang P, Yu S, Li H, et al. ILT4 drives B7-H3 expression via PI3K/AKT/mTOR signalling and ILT4/B7-H3 co-expression correlates with poor prognosis in non-small cell lung cancer. FEBS Lett. 2015;589:2248–56.CrossRefPubMedGoogle Scholar
  12. 12.
    Zhang P, Guo X, Li J, et al. Immunoglobulin-like transcript 4 promotes tumor progression and metastasis and up-regulates VEGF-C expression via ERK signaling pathway in non-small cell lung cancer. Oncotarget. 2015;6:13550–63.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Wang L, Geng T, Guo X, et al. Co-expression of immunoglobulin-like transcript 4 and angiopoietin-like proteins in human non-small cell lung cancer. Mol Med Rep. 2015;11:2789–96.PubMedGoogle Scholar
  14. 14.
    Curigliano G, Criscitiello C, Gelao L, Goldhirsch A. Molecular pathways: human leukocyte antigen G (HLA-G). Clin Cancer Res. 2013;19:5564–71.CrossRefPubMedGoogle Scholar
  15. 15.
    Carosella ED, Favier B, Rouas-Freiss N, Moreau P, Lemaoult J. Beyond the increasing complexity of the immunomodulatory HLA-G molecule. Blood. 2008;111:4862–70.CrossRefPubMedGoogle Scholar
  16. 16.
    Le Discorde M, Moreau P, Sabatier P, Legeais JM, Carosella ED. Expression of HLA-G in human cornea, an immune-privileged tissue. Hum Immunol. 2003;64:1039–44.CrossRefPubMedGoogle Scholar
  17. 17.
    Rebmann V, Da SNF, Wagner B, Horn PA. HLA-G as a tolerogenic molecule in transplantation and pregnancy. J Immunol Res. 2014;2014:297073.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Menier C, Rabreau M, Challier JC, Le Discorde M, Carosella ED, Rouas-Freiss N. Erythroblasts secrete the nonclassical HLA-G molecule from primitive to definitive hematopoiesis. Blood. 2004;104:3153–60.CrossRefPubMedGoogle Scholar
  19. 19.
    Lefebvre S, Adrian F, Moreau P, et al. Modulation of HLA-G expression in human thymic and amniotic epithelial cells. Hum Immunol. 2000;61:1095–101.CrossRefPubMedGoogle Scholar
  20. 20.
    Dias FC, Castelli EC, Collares CV, Moreau P, Donadi EA. The role of HLA-G molecule and HLA-G gene polymorphisms in tumors, viral hepatitis, and parasitic diseases. Front Immunol. 2015;6:9.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Amiot L, Ferrone S, Grosse-Wilde H, Seliger B. Biology of HLA-G in cancer: a candidate molecule for therapeutic intervention? Cell Mol Life Sci. 2011;68:417–31.CrossRefPubMedGoogle Scholar
  22. 22.
    Yie S, Yang H, Ye S, Li K, Dong D, Lin X. Expression of human leucocyte antigen G (HLA-G) is associated with prognosis in non-small cell lung cancer. Lung Cancer J Iaslc. 2007;58:267–74.CrossRefGoogle Scholar
  23. 23.
    Lin A, Zhu CC, Chen HX, et al. Clinical relevance and functional implications for human leucocyte antigen-g expression in non-small-cell lung cancer. J Cell Mol Med. 2010;14:2318–29.CrossRefPubMedGoogle Scholar
  24. 24.
    Agaugue S, Carosella ED, Rouas-Freiss N. Role of HLA-G in tumor escape through expansion of myeloid-derived suppressor cells and cytokinic balance in favor of Th2 versus Th1/Th17. Blood. 2011;117:7021–31.CrossRefPubMedGoogle Scholar
  25. 25.
    Tuncel T, Karagoz B, Haholu A, et al. Immunoregulatory function of HLA-G in gastric cancer. Asian Pac J Cancer Prev. 2013;14:7681–4.CrossRefPubMedGoogle Scholar
  26. 26.
    Loumagne L, Baudhuin J, Favier B, Montespan F, Carosella ED, Rouas-Freiss N. In vivo evidence that secretion of HLA-G by immunogenic tumor cells allows their evasion from immunosurveillance. Int J Cancer. 2014;135:2107–17.CrossRefPubMedGoogle Scholar
  27. 27.
    Du L, Xiao X, Wang C, et al. Human leukocyte antigen-G is closely associated with tumor immune escape in gastric cancer by increasing local regulatory T cells. Cancer Sci. 2011;102:1272–80.CrossRefPubMedGoogle Scholar
  28. 28.
    Zheng J, Umikawa M, Cui C, et al. Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development. Nature. 2012;485:656–60.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Sporn MB, Roberts AB. Autocrine growth factors and cancer. Nature. 1985;313:745–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Brand TM, Iida M, Luthar N, Starr MM, Huppert EJ, Wheeler DL. Nuclear EGFR as a molecular target in cancer. Radiother Oncol. 2013;108:370–7.CrossRefPubMedGoogle Scholar
  31. 31.
    You B, Yang YL, Xu Z, et al. Inhibition of ERK1/2 down-regulates the Hippo/YAP signaling pathway in human NSCLC cells. Oncotarget. 2015;6:4357–68.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kitano H, Chung JY, Ylaya K, et al. Profiling of phospho-AKT, phospho-mTOR, phospho-MAPK and EGFR in non-small cell lung cancer. J Histochem Cytochem. 2014;62:335–46.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Molina JR, Adjei AA. The Ras/Raf/MAPK pathway. J Thorac Oncol. 2006;1:7–9.CrossRefPubMedGoogle Scholar
  34. 34.
    Zimmer S, Kahl P, Buhl TM, et al. Epidermal growth factor receptor mutations in non-small cell lung cancer influence downstream Akt, MAPK and Stat3 signaling. J Cancer Res Clin Oncol. 2009;135:723–30.CrossRefPubMedGoogle Scholar
  35. 35.
    Martinez-Lopez N, Singh R. ATGs: scaffolds for MAPK/ERK signaling. Autophagy. 2014;10:535–7.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Sethi G, Ahn KS, Chaturvedi MM, Aggarwal BB. Epidermal growth factor (EGF) activates nuclear factor-kappaB through IkappaBalpha kinase-independent but EGF receptor-kinase dependent tyrosine 42 phosphorylation of IkappaBalpha. Oncogene. 2007;26:7324–32.CrossRefPubMedGoogle Scholar
  37. 37.
    Guillard C, Zidi I, Marcou C, Menier C, Carosella ED, Moreau P. Role of HLA-G in innate immunity through direct activation of NF-kappaB in natural killer cells. Mol Immunol. 2008;45:419–27.CrossRefPubMedGoogle Scholar
  38. 38.
    Zidi I, Guillard C, Carosella ED, Moreau P. Soluble HLA-G induces NF-kappaB activation in natural killer cells. J Physiol Biochem. 2010;66:39–46.CrossRefPubMedGoogle Scholar
  39. 39.
    Guo Y, Lee CL, So KH, et al. Soluble human leukocyte antigen-g5 activates extracellular signal-regulated protein kinase signaling and stimulates trophoblast invasion. PLoS One. 2013;8, e76023.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Wang JM, Zhao HX, Wang L, Gao ZY, Yao YQ. The human leukocyte antigen G promotes trophoblast fusion and beta-hCG production through the Erk1/2 pathway in human choriocarcinoma cell lines. Biochem Biophys Res Commun. 2013;434:460–5.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Yanwen Zhang
    • 1
    • 2
  • Jianqiang Zhao
    • 2
  • Lijun Qiu
    • 3
  • Pei Zhang
    • 2
  • Juan Li
    • 2
  • Dong Yang
    • 2
  • Xiaojuan Wei
    • 2
  • Yali Han
    • 2
  • Siyue Nie
    • 2
  • Yuping Sun
    • 2
  1. 1.Department of Oncology, School of MedicineShandong UniversityJinanChina
  2. 2.Department of Oncology, Jinan Central HospitalShandong UniversityJinanChina
  3. 3.Department of Pharmacy, Jinan Central HospitalShandong UniversityJinanChina

Personalised recommendations