title: Role of microRNAs in resveratrol-mediated mitigation of colitis-associated tumorigenesis in Apc(Min/+) mice.
abstract: The pleiotropic effects of resveratrol include anti-inflammatory, antioxidant, and anticancer activities, and thus unique possibilities exist to explore mechanistic pathways of chemoprevention. The aim of this study was to investigate the role of microRNA (miRNA) alterations induced by resveratrol in the context of chemopreventive mechanisms against dextran sodium sulfate (DSS)-induced colitis-associated tumorigenesis in the Apc(Min/+) mouse. To that end, Apc(Min/+) mice were exposed to 2% DSS to enhance intestinal inflammation and polyp development. Concurrently, mice received either vehicle or resveratrol treatment via oral gavage for 5 weeks. Interestingly, treatment of DSS-exposed mice with resveratrol resulted in decreased number and size of polyps, fewer histologic signs of cell damage, and decreased proliferating epithelial cells in intestinal mucosa compared with vehicle. Resveratrol treatment dramatically reversed the effects of DSS on the numbers of specific inflammatory CD4(+) T cells, CD8(+) T cells, B cells, natural killer T cells, and myeloid-derived suppressor cells in mesenteric lymph nodes. Resveratrol treatment also decreased interleukin-6 (IL-6) and tumor necrosis factor-α protein levels and reduced IL-6 and cyclooxygenase-2 mRNA expression. Microarray analysis revealed 104 miRNAs exhibiting >1.5-fold differences in expression in the intestinal tissue of resveratrol-treated mice. Among them, two miRNAs with anti-inflammatory properties, miRNA-101b and miRNA-455, were validated to be upregulated with resveratrol treatment by reverse-transcription polymerase chain reaction. Pathway analysis revealed that numerous differentially regulated miRNAs targeted mRNAs associated with inflammatory processes with known roles in intestinal tumorigenesis. These results suggest that resveratrol mediates anti-inflammatory properties and suppresses intestinal tumorigenesis through miRNA modulation.
authors.affiliation: Department of Pathology, Microbiology, and Immunology, School of Medicine (I.A., E.A.M., J.F.C., E.E.Z., J.L.M., U.P.S., P.S.N., M.N.) and Arnold School of Public Health (J.Z.), University of South Carolina, Columbia, South Carolina.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Altamemi
authors.affiliation: Department of Pathology, Microbiology, and Immunology, School of Medicine (I.A., E.A.M., J.F.C., E.E.Z., J.L.M., U.P.S., P.S.N., M.N.) and Arnold School of Public Health (J.Z.), University of South Carolina, Columbia, South Carolina.
authors.forename: E Angela
authors.initials: EA
authors.lastname: Murphy
authors.affiliation: Department of Pathology, Microbiology, and Immunology, School of Medicine (I.A., E.A.M., J.F.C., E.E.Z., J.L.M., U.P.S., P.S.N., M.N.) and Arnold School of Public Health (J.Z.), University of South Carolina, Columbia, South Carolina.
authors.forename: James F
authors.initials: JF
authors.lastname: Catroppo
authors.affiliation: Department of Pathology, Microbiology, and Immunology, School of Medicine (I.A., E.A.M., J.F.C., E.E.Z., J.L.M., U.P.S., P.S.N., M.N.) and Arnold School of Public Health (J.Z.), University of South Carolina, Columbia, South Carolina.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Zumbrun
authors.affiliation: Department of Pathology, Microbiology, and Immunology, School of Medicine (I.A., E.A.M., J.F.C., E.E.Z., J.L.M., U.P.S., P.S.N., M.N.) and Arnold School of Public Health (J.Z.), University of South Carolina, Columbia, South Carolina.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Microbiology, and Immunology, School of Medicine (I.A., E.A.M., J.F.C., E.E.Z., J.L.M., U.P.S., P.S.N., M.N.) and Arnold School of Public Health (J.Z.), University of South Carolina, Columbia, South Carolina.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: McClellan
authors.affiliation: Department of Pathology, Microbiology, and Immunology, School of Medicine (I.A., E.A.M., J.F.C., E.E.Z., J.L.M., U.P.S., P.S.N., M.N.) and Arnold School of Public Health (J.Z.), University of South Carolina, Columbia, South Carolina.
authors.forename: Udai P
authors.initials: UP
authors.lastname: Singh
authors.affiliation: Department of Pathology, Microbiology, and Immunology, School of Medicine (I.A., E.A.M., J.F.C., E.E.Z., J.L.M., U.P.S., P.S.N., M.N.) and Arnold School of Public Health (J.Z.), University of South Carolina, Columbia, South Carolina.
authors.forename: Prakash S
authors.initials: PS
authors.lastname: Nagarkatti
authors.affiliation: Department of Pathology, Microbiology, and Immunology, School of Medicine (I.A., E.A.M., J.F.C., E.E.Z., J.L.M., U.P.S., P.S.N., M.N.) and Arnold School of Public Health (J.Z.), University of South Carolina, Columbia, South Carolina Mitzi.Nagarkatti@uscmed.sc.edu.
authors.forename: Mitzi
authors.initials: M
authors.lastname: Nagarkatti
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003111:Colonic Polyps / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D016264:Dextran Sulfate; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D015850:Interleukin-6 / Q000378:metabolism; D007417:Intestinal Polyps / Q000188:drug therapy; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D035683:MicroRNAs / Q000378:metabolism*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D035683:MicroRNAs; D013267:Stilbenes; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate; D051546:Cyclooxygenase 2; D000077185:Resveratrol