title: Inhibition of MMP activity can restore NKG2D ligand expression in gastric cancer, leading to improved NK cell susceptibility.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Surgery, National University of Singapore, Singapore, Singapore.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Shiraishi
authors.affiliation: Department of Surgery, National University of Singapore, Singapore, Singapore.
authors.forename: Kousaku
authors.initials: K
authors.lastname: Mimura
authors.affiliation: Department of Hematology-Oncology, National University of Singapore, Singapore, Singapore.
authors.forename: Ley-Fang
authors.initials: LF
authors.lastname: Kua
authors.affiliation: Department of Hematology-Oncology, National University of Singapore, Singapore, Singapore.
authors.forename: Vivien
authors.initials: V
authors.lastname: Koh
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Lim Kee
authors.initials: LK
authors.lastname: Siang
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Nakajima
authors.affiliation: First Department of Surgery, University of Yamanashi, Kofu, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujii
authors.affiliation: Department of Surgery, National University of Singapore, Singapore, Singapore.
authors.forename: Asim
authors.initials: A
authors.lastname: Shabbir
authors.affiliation: Department of Hematology-Oncology, National University of Singapore, Singapore, Singapore.
authors.forename: Wei-Peng
authors.initials: WP
authors.lastname: Yong
authors.affiliation: Department of Surgery, National University of Singapore, Singapore, Singapore.
authors.forename: Jimmy
authors.initials: J
authors.lastname: So
authors.affiliation: Department of Advanced Cancer Immunotherapy, Fukushima Medical University, 1 Hikarigaoka, Fukushima City, 960-1295, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Takenoshita
authors.affiliation: Department of Surgery, National University of Singapore, Singapore, Singapore. kojikono@fmu.ac.jp.|Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. kojikono@fmu.ac.jp.|Department of Advanced Cancer Immunotherapy, Fukushima Medical University, 1 Hikarigaoka, Fukushima City, 960-1295, Japan. kojikono@fmu.ac.jp.|Department of Organ Regulatory Surgery, Fukushima Medical University, 1 Hikarigaoka, Fukushima City, 960-1295, Japan. kojikono@fmu.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Kono
mesh_terms: D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D015536:Down-Regulation / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C527085:KLRK1 protein, human; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D055655:NK Cell Lectin-Like Receptor Subfamily K; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9
keywords: Gastric cancer; MHC class I chain-related A/MHC class I chain-related B; Matrix metalloproteinases; Natural killer cells; UL16-binding proteins