title: Resveratrol modulates the levels of microRNAs targeting genes encoding tumor-suppressors and effectors of TGFβ signaling pathway in SW480 cells.
abstract: Resveratrol (trans-3,4',5-trihydroxystilbene) is a natural antioxidant with cardiovascular and cancer preventive properties that is currently at the stage of pre-clinical studies for human cancer prevention. Beside its known effects on protein coding genes, one possible mechanism for resveratrol protective activities is by modulating the levels of non-coding RNAs. Here, we analyzed the effects of resveratrol on microRNA populations in human SW480 colon cancer cells. We establish that resveratrol treatment decreases the levels of several oncogenic microRNAs targeting genes encoding Dicer1, a cytoplasmic RNase III producing mature microRNAs from their immediate precursors, tumor-suppressor factors such as PDCD4 or PTEN, as well as key effectors of the TGFβ signaling pathway, while increasing the levels of miR-663, a tumor-suppressor microRNA targeting TGFβ1 transcripts. We also show that, while upregulating several components of the TGFβ signaling pathway such as TGFβ receptors type I (TGFβR1) and type II (TGFβR2), resveratrol decreases the transcriptional activity of SMADs, the main effectors of the canonical TGFβ pathway. Our results establish that protective properties of resveratrol may arise at least in part from its capability to modify the composition of microRNA populations in cells, and suggest that the manipulation of the levels of key microRNAs, such as miR-663, may help to potentiate the anti-cancer and anti-metastatic effects of resveratrol.
authors.affiliation: Ohio State University, Department of Molecular Virology, Immunology and Medical Genetics, 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: Hansjuerg
authors.initials: H
authors.lastname: Alder
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
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: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D000077185:Resveratrol; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; C552243:MIRN663 microRNA, human; D035683:MicroRNAs; D015513:Oncogene Proteins; D051785:Smad Proteins; D013267:Stilbenes; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins; D000077185:Resveratrol