Role of microRNAs in Resveratrol-Mediated Mitigation of Colitis-Associated Tumorigenesis inApc^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/1 mouse. To that end, ApcMin/1 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 1 T cells, CD8 1 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-a 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.

A multi-targeted approach to suppress tumor-promoting inflammation

“…For example, through the inhibition of NF-κB, resveratrol ameliorates diabetic vascular inflammation and macrophage infiltration in diabetic mice, inhibits the epithelial-mesenchymal transition, modulates autophagy, suppresses cell transformation, regulates miRNA levels, and reverses resistance to chemotherapeutic agents [399–405]. Notably, resveratrol has also been shown to inhibit other key modulators of inflammation and cancer discussed in this review, including COX-2 [406–408], MIF [409], TNF-α [410], iNOS [411], AKT [412], and the CXC group of cytokines [413].…”

Resveratrol modulates the gut microbiota to prevent murine colitis development through induction of Tregs and suppression of Th17 cells

“…Resveratrol (3,4,5‐trihydroxy‐trans‐stilbene) is a natural polyphenol produced by several plants in response to injury or when the plant is under attack by pathogens such as bacteria or fungi . Resveratrol has been extensively studied for its therapeutic benefits against a wide array of diseases including cancer, cardiovascular, neurological, and inflammatory diseases . Resveratrol mediates these anti‐inflammatory effects through multiple pathways .…”

“…For example, resveratrol has been shown to attenuate colitis by up‐regulating silent mating type information regulation‐1 (SIRT1) in immune cells, which is associated with the T regulatory cells (Treg) induction and activation of hypoxia‐inducible Factor 1α (HIF‐1α)/MTor signaling pathway . Resveratrol has also been shown to induce unique microRNA that trigger anti‐inflammatory pathways as well as induce myeloid‐derived suppressor cells (MDSCs) . While resveratrol has been shown to alter the gut microbiome in various disease models, these studies have captured only an association between resveratrol‐induced modulations in gut microbiota and the disease outcome.…”

Kaempferol inhibits vascular smooth muscle cell migration by modulating BMP-mediated miR-21 expression

“…Recent studies reported that dietary polyphenols modulate expression of several miRNAs and may indirectly modulate the epigenome by miRNAs that target specific epigenetic modifier enzymes [20]. For example, resveratroltreated mice exhibit differential expression levels of 104 miRNAs in the intestinal tissue [22]. Moreover, resveratrol mediates anti-inflammatory properties and suppresses intestinal tumorigenesis by modulating miR-101b and miR-455.…”