Abstract
The alterations induced in dendritic cells (DCs) in the cancer microenvironment have not been extensively explored. We found that the tumor-associated factor TGF-β may selectively upregulate the expression of miR-27a via the SP1 transcription factor. Importantly, miR-27a altered the activity of NF-κB and MAPKs (mitogen-activated protein kinases) p38, JNK (c-Jun N-terminal kinases) and ERK (extracellular signal-regulated kinase 1/2). It influences the production of proinflammatory cytokines by targeting TAB3, p38 MAPK, MAP2K4 and MAP2K7. As a consequence, miR-27a hampered the DC-mediated differentiation of Th1 and Th17 cells in vitro and in vivo, but it promoted the DC-mediated accumulation of Tr1 (CD4(+)IL-10(+)) and Treg (CD4(+)CD25(+)Foxp3(+)) cells in vivo. The repeated infusion of miR-27a-engineered DCs into tumor tissues accelerated tumor growth, indicating that miR-27a is a potential target for tumor immunotherapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Base Sequence
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Cell Communication
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Cell Differentiation
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Cell Line, Tumor
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Dendritic Cells / drug effects
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Dendritic Cells / metabolism*
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Dendritic Cells / pathology
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Gene Expression Regulation, Neoplastic
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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MAP Kinase Signaling System
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Macrophages / drug effects
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Macrophages / metabolism
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Macrophages / pathology
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Mice
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MicroRNAs / genetics*
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MicroRNAs / metabolism
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Mitogen-Activated Protein Kinases / genetics*
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Mitogen-Activated Protein Kinases / metabolism
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Molecular Sequence Data
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Monocytes / drug effects
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Monocytes / metabolism
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Monocytes / pathology
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Oligonucleotide Array Sequence Analysis
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Signal Transduction
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Th1 Cells / drug effects
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Th1 Cells / metabolism*
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Th1 Cells / pathology
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Th17 Cells / drug effects
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Th17 Cells / metabolism*
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Th17 Cells / pathology
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Transforming Growth Factor beta / metabolism
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Transforming Growth Factor beta / pharmacology*
Substances
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Adaptor Proteins, Signal Transducing
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Intracellular Signaling Peptides and Proteins
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MIRN27 microRNA, human
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MicroRNAs
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TAB3 protein, human
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Transforming Growth Factor beta
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Mitogen-Activated Protein Kinases