title: Resveratrol decreases the levels of miR-155 by upregulating miR-663, a microRNA targeting JunB and JunD.
abstract: An inflammatory component is present in the microenvironment of most neoplastic tissues, including those not causally related to an obvious inflammatory process. Several microRNAs, and especially miR-155, play an essential role in both the innate and adaptative immune response. Resveratrol (trans-3,4',5-trihydroxystilbene) is a natural antioxidant with anti-inflammatory properties that is currently at the stage of preclinical studies for human cancer prevention. Here, we establish that, in human THP-1 monocytic cells as well as in human blood monocytes, resveratrol upregulates miR-663, a microRNA potentially targeting multiple genes implicated in the immune response. In THP-1 cells, miR-663 decreases endogenous activator protein-1 (AP-1) activity and impairs its upregulation by lipopolysaccharides (LPS), at least in part by directly targeting JunB and JunD transcripts. We further establish that the downregulation of AP-1 activity by resveratrol is miR-663 dependent and that the effects of resveratrol on both AP-1 activity and JunB levels are dose dependent. Finally, we show that resveratrol impairs the upregulation of miR-155 by LPS in a miR-663-dependent manner. Given the role of miR-155 in the innate immune response and the fact that it is upregulated in many cancers, our results suggest that manipulating miR-663 levels may help to optimize the use of resveratrol as both an anti-inflammatory and anticancer agent against malignancies associated with high levels of miR-155.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Biomedical Tower, 460 West 12th Avenue, Columbus, OH 43210, USA.
authors.forename: Esmerina
authors.initials: E
authors.lastname: Tili
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Michaille
authors.forename: Brett
authors.initials: B
authors.lastname: Adair
authors.forename: Hansjuerg
authors.initials: H
authors.lastname: Alder
authors.forename: Emeric
authors.initials: E
authors.lastname: Limagne
authors.forename: Cristian
authors.initials: C
authors.lastname: Taccioli
authors.forename: Manuela
authors.initials: M
authors.lastname: Ferracin
authors.forename: Dominique
authors.initials: D
authors.lastname: Delmas
authors.forename: Norbert
authors.initials: N
authors.lastname: Latruffe
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013267:Stilbenes / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D008070:Lipopolysaccharides; C524942:MIRN155 microRNA, human; C552243:MIRN663 microRNA, human; D035683:MicroRNAs; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D013267:Stilbenes; D018808:Transcription Factor AP-1; D008156:Luciferases; D000077185:Resveratrol