Abstract
Constitutive activation of Notch signaling was found in melanoma cells. Using siRNA specifically knocking down Notch co-activator MAML1 blocked Notch down stream transcriptional repressor Hey1 expression, significantly upregulated TweakR and CCL2 mRNA and protein expression in melanoma cell line M624. Exogenous Tweak stimulated high level CCL2 production in siMAML transfected M624 cells, which was critically dependent on Tweak-TweakR ligation. CCL2 produced by siMAML1 transfected M624 stimulated with exogenous Tweak was functional chemoattractant to activated monocytes. This study supports targeting Notch signaling using small siRNA in melanoma cells may increase immune cell recruitment and restore natural immune surveillance in tumor microenvironment.
MeSH terms
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Cell Line, Tumor
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Cell Movement
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Chemokine CCL2 / biosynthesis*
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Chemokine CCL2 / genetics
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Gene Expression
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Humans
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Melanoma / immunology*
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Monocytes / immunology
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Protein Biosynthesis
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RNA, Small Interfering / genetics
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Receptors, Notch / antagonists & inhibitors*
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Receptors, Notch / genetics
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Receptors, Notch / metabolism
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Receptors, Tumor Necrosis Factor / metabolism*
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Repressor Proteins / metabolism
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Signal Transduction
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Skin Neoplasms / immunology*
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TWEAK Receptor
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Trans-Activators
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Transcription Factors
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Up-Regulation
Substances
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Basic Helix-Loop-Helix Transcription Factors
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CCL2 protein, human
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Chemokine CCL2
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DNA-Binding Proteins
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Hairy, HRT1 protein
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MAML1 protein, human
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Nuclear Proteins
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RNA, Small Interfering
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Receptors, Notch
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Receptors, Tumor Necrosis Factor
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Repressor Proteins
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TWEAK Receptor
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Trans-Activators
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Transcription Factors