Kensuke Shiraishi1, Kousaku Mimura1, Ley-Fang Kua2, Vivien Koh2, Lim Kee Siang3, Shotaro Nakajima3, Hideki Fujii4, Asim Shabbir1, Wei-Peng Yong2, Jimmy So1, Seiichi Takenoshita5, Koji Kono6,7,8,9. 1. Department of Surgery, National University of Singapore, Singapore, Singapore. 2. Department of Hematology-Oncology, National University of Singapore, Singapore, Singapore. 3. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. 4. First Department of Surgery, University of Yamanashi, Kofu, Japan. 5. Department of Advanced Cancer Immunotherapy, Fukushima Medical University, 1 Hikarigaoka, Fukushima City, 960-1295, Japan. 6. Department of Surgery, National University of Singapore, Singapore, Singapore. kojikono@fmu.ac.jp. 7. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. kojikono@fmu.ac.jp. 8. Department of Advanced Cancer Immunotherapy, Fukushima Medical University, 1 Hikarigaoka, Fukushima City, 960-1295, Japan. kojikono@fmu.ac.jp. 9. Department of Organ Regulatory Surgery, Fukushima Medical University, 1 Hikarigaoka, Fukushima City, 960-1295, Japan. kojikono@fmu.ac.jp.
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.
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 clinicaltumor 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.
Entities:
Keywords:
Gastric cancer; MHC class I chain-related A/MHC class I chain-related B; Matrix metalloproteinases; Natural killer cells; UL16-binding proteins
Authors: Alejandro Godoy-Pacheco; Mariel García-Chagollán; Adrián Ramírez-De-Arellano; Christian David Hernández-Silva; Julio César Villegas-Pineda; Inocencia Guadalupe Ramírez-López; José Sergio Zepeda-Nuño; Adriana Aguilar-Lemarroy; Ana Laura Pereira-Suárez Journal: Oncol Lett Date: 2022-06-28 Impact factor: 3.111
Authors: Alexandra Frazao; Louise Rethacker; Meriem Messaoudene; Marie-Françoise Avril; Antoine Toubert; Nicolas Dulphy; Anne Caignard Journal: Front Immunol Date: 2019-03-29 Impact factor: 7.561