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Inhibition of MMP activity can restore NKG2D ligand expression in gastric cancer, leading to improved NK cell susceptibility

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Abstract

Background and methods

Natural killer (NK) cells can react with tumor cells through the balance of inhibitory and stimulatory signals between NK cell surface receptors and their ligands, such as MHC class I chain-related A (MICA), MHC class I chain-related B (MICB), and several UL16-binding proteins (ULBPs). In the present study, we evaluated the relationship between NKG2D ligand expression and matrix metalloproteinase (MMP) activity in in vitro culture systems of a panel of gastric cancer cell lines (n = 10) and clinical samples (n = 102).

Results

First, the surface expression of NK group 2 member D (NKG2D) ligands (MICA, MICB, ULBP-2, and ULBP-3) on tumor cells was markedly downregulated on in vitro culture, in parallel to the upregulation of MMPs analyzed by gelatin zymography and gene expression microarray, whereas the transcript levels of NKG2D ligands remained unchanged on in vitro culture. Second, MMP-specific inhibitors could restore the downregulated expression of NKG2D ligands and functionally improve susceptibilities to NK cells in vitro. Third, the production of soluble NKG2D ligands was increased on in vitro culture and was inhibited by MMP-specific inhibitors. Finally, there was a significant inverse correlation between MMP-9 expression and NKG2D ligand expression as analyzed by immunohistochemistry in clinical tumor samples.

Conclusion

The present study is a comprehensive study demonstrating that upregulation of MMP activity can induce a downregulation of expression of NKG2D ligands in gastric cancer cells, leading to lower-level susceptibility to NK cells.

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Acknowledgments

This work was supported by a Clinician Scientist Award and Clinician Scientist Individual Research Grant from the National Medical Research Council of Singapore.

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Authors and Affiliations

  1. Department of Surgery, National University of Singapore, Singapore, Singapore

    Kensuke Shiraishi, Kousaku Mimura, Asim Shabbir, Jimmy So & Koji Kono

  2. Department of Hematology-Oncology, National University of Singapore, Singapore, Singapore

    Ley-Fang Kua, Vivien Koh & Wei-Peng Yong

  3. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore

    Lim Kee Siang, Shotaro Nakajima & Koji Kono

  4. First Department of Surgery, University of Yamanashi, Kofu, Japan

    Hideki Fujii

  5. Department of Advanced Cancer Immunotherapy, Fukushima Medical University, 1 Hikarigaoka, Fukushima City, 960-1295, Japan

    Seiichi Takenoshita & Koji Kono

  6. Department of Organ Regulatory Surgery, Fukushima Medical University, 1 Hikarigaoka, Fukushima City, 960-1295, Japan

    Koji Kono

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  1. Kensuke Shiraishi
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  2. Kousaku Mimura
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Correspondence to Koji Kono.

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Shiraishi, K., Mimura, K., Kua, LF. et al. Inhibition of MMP activity can restore NKG2D ligand expression in gastric cancer, leading to improved NK cell susceptibility. J Gastroenterol 51, 1101–1111 (2016). https://doi.org/10.1007/s00535-016-1197-x

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  • DOI: https://doi.org/10.1007/s00535-016-1197-x

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