Abstract
The Toll-like receptor 9 (TLR9) evolved to cope with pathogens, but it is expressed in a variety of tumors for reasons that are unclear. In this study, we report that neuroblastoma (NB) cells express functional TLR9. Liposome-complexed CpG oligonucleotides inhibited the proliferation of TLR9-expressing NB cells and induced caspase-dependent apoptotic cell death. Inhibitory oligonucleotides (iODNs) abrogated these effects. RNA interference reduced TLR9 expression but not to the level where functional responses to CpG were abolished. Compared with free CpG, liposomal formulations of NB-targeted CpG (TL-CpG) significantly prolonged the survival of mice bearing NB tumor xenografts. While CpG alone lacked antitumor efficacy in NOD/SCID/IL2rg(-/-) mice, TL-CpG retained significant efficacy related to direct effects on tumor cells. TLR9 expression in primary human NB specimens was found to correlate inversely with disease stage. Our findings establish functional expression of TLR9 in NB and suggest that TLR9 may represent a novel theranostic target in this disease.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects*
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Blotting, Western
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Infant
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Interleukin Receptor Common gamma Subunit / deficiency
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Interleukin Receptor Common gamma Subunit / genetics
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Liposomes / chemistry
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Mice
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Mice, Inbred NOD
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Mice, Knockout
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Mice, Nude
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Mice, SCID
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Neoplasm Staging
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Neuroblastoma / genetics
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Neuroblastoma / pathology
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Neuroblastoma / therapy*
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Oligodeoxyribonucleotides / genetics
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Oligodeoxyribonucleotides / pharmacology*
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Oligodeoxyribonucleotides, Antisense / chemistry
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Oligodeoxyribonucleotides, Antisense / genetics
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Oligodeoxyribonucleotides, Antisense / pharmacology
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RNA Interference*
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Reverse Transcriptase Polymerase Chain Reaction
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Survival Analysis
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Toll-Like Receptor 9 / antagonists & inhibitors*
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Toll-Like Receptor 9 / genetics
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Toll-Like Receptor 9 / metabolism
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Xenograft Model Antitumor Assays
Substances
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CPG-oligonucleotide
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Il2rg protein, mouse
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Interleukin Receptor Common gamma Subunit
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Liposomes
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Oligodeoxyribonucleotides
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Oligodeoxyribonucleotides, Antisense
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Toll-Like Receptor 9