Abstract
Midkine (MK) is a heparin-binding growth factor overexpressed in various human cancers. In the current study, a positive correlation was observed between MK expression and MICA/B serum levels of gastric cancer patients. In addition, MK transfection significantly increased MICA/B expression in gastric cancer cells. The soluble MICA/B expression was also elevated. Furthermore, MK transfection inhibited CD107a and Granzyme B expression, thereby suppressing the natural killer (NK) cell cytotoxicity in vitro. The phosphorylation of p38 MAPK and its promotion of CHOP expression were also observed after MK treatment and transfection. CHOP was indirectly bound to the MICA/B promoter region by interacting with AP-1, leading to MICA/B transcription. Overall, the current study shows that MK expression in tumor cells indirectly suppresses NK cytotoxicity by inducing MICA/B expression and suppressing NKG2D expression.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / blood
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism*
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Cell Line, Tumor
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Female
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Granzymes / biosynthesis
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Histocompatibility Antigens Class I / biosynthesis*
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Histocompatibility Antigens Class I / blood
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Histocompatibility Antigens Class I / genetics
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Humans
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Killer Cells, Natural / immunology*
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Killer Cells, Natural / metabolism
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Lysosomal-Associated Membrane Protein 1 / biosynthesis
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Male
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Middle Aged
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Midkine
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NK Cell Lectin-Like Receptor Subfamily K / biosynthesis
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Nerve Growth Factors / blood
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Nerve Growth Factors / genetics
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Nerve Growth Factors / metabolism*
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Phosphorylation
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Promoter Regions, Genetic
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Stomach Neoplasms / blood
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Stomach Neoplasms / genetics
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Stomach Neoplasms / metabolism*
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Transcription Factor AP-1 / chemistry
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Transcription Factor AP-1 / metabolism
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Transcription Factor CHOP / biosynthesis
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Transfection
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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DDIT3 protein, human
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Histocompatibility Antigens Class I
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Lysosomal-Associated Membrane Protein 1
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MDK protein, human
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MHC class I-related chain A
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MICB antigen
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NK Cell Lectin-Like Receptor Subfamily K
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Nerve Growth Factors
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Transcription Factor AP-1
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Midkine
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Transcription Factor CHOP
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p38 Mitogen-Activated Protein Kinases
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Granzymes