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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

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Tumor Biology

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.

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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

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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.

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Authors and Affiliations

  1. Department of Oncology, School of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong, 250012, China

    Yanwen Zhang

  2. Department of Oncology, Jinan Central Hospital, Shandong University, 105 Jie Fang Road, Jinan, Shandong, 250013, China

    Yanwen Zhang, Jianqiang Zhao, Pei Zhang, Juan Li, Dong Yang, Xiaojuan Wei, Yali Han, Siyue Nie & Yuping Sun

  3. Department of Pharmacy, Jinan Central Hospital, Shandong University, 105 Jie Fang Road, Jinan, Shandong, 250013, China

    Lijun Qiu

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  1. Yanwen Zhang
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Correspondence to Yuping Sun.

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Zhang, Y., Zhao, J., Qiu, L. et al. 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. Tumor Biol. 37, 11187–11198 (2016). https://doi.org/10.1007/s13277-016-5002-5

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  • DOI: https://doi.org/10.1007/s13277-016-5002-5

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