Resveratrol suppresses ulcerative colitis and colitis-associated colorectal cancer via modulating the miR-31-5p/SATB2 axis

Abstract

BACKGROUND

Ulcerative colitis (UC) can progress to colitis-associated colorectal cancer (CAC), but the transition mechanisms including the role of microRNAs are largely unknown and there is no effective pharmacotherapy for the diseases.

AIM

To elucidate the role of miR-31-5p/special AT-rich sequence-binding protein 2 (SATB2) axis in UC-to-CAC transition and evaluate the therapeutic effect of resveratrol (Res) on CAC.

METHODS

MiR-31-5p expressions in human colorectal cancer (CRC) tissues and human UC mucosa were analyzed. The effects of miR-31-5p mimics and inhibitors on HCT116 cell migration, proliferation, apoptosis, and nuclear factor (NF)-κB/Bcl-2/Bax signaling were examined. Colitis was induced by dextran sulfate sodium in miR-31 transgenic mice. Bioinformatics and dual-luciferase assays were performed to identify the target of miR-31-5p. The potential therapeutic effect of Res on CAC was investigated in mice and HCT116 cells.

RESULTS

Analysis of The Cancer Genome Atlas-Colon Adenocarcinoma human CRC data (n = 603 for CRC, n = 11 for normal control) and a preliminary human UC cohort (n = 4) revealed significant elevation of miR-31-5p in diseased tissues. In HCT116 CRC cells, miR-31-5p mimics promoted tumor cell migration/proliferation, inhibited apoptosis, activated NF-κB, and increased the Bcl-2/Bax ratio, whereas miR-31-5p inhibitors showed the opposite effects. miR-31 transgenic mice showed more severe dextran sulfate sodium-induced colitis as manifested by weight loss, colon shortening, splenomegaly and colon injury, and elevations of pro-inflammatory [cyclooxygenase-2, iNOS, tumor necrosis factor-α, Toll-like receptor-4 (TLR4), NF-κB] and pro-apoptotic (cytochrome C, caspase-9/3) proteins and colon cell apoptosis. miR-31-5p directly targeted and suppressed SATB2 via binding to its 3’-untranslated region, suggesting SATB2 is a functional target of miR-31-5p. SATB2 overexpression partially counteracted the oncogenic effects of miR-31-5p. Res treatment suppressed CRC growth both in mice in vivo and in HCT116 cells in vitro by downregulating miR-31-5p, restoring SATB2 expression, and inhibiting TLR4/NF-κB signaling.

CONCLUSION

MiR-31-5p is an oncogenic molecule and drives UC-to-CAC transition by suppressing SATB2 expression, activating TLR4/NF-κB signaling, and inhibiting apoptosis. Res exerts a therapeutic effect on UC-to-CAC progression by suppressing the miR-31-5p/SATB2 axis.

Keywords: MiR-31-5p; Special AT-rich sequence-binding protein 2; Ulcerative colitis; Colitis-associated cancer; Azoxymethane; Dextran sulphate sodium; Resveratrol

Core Tip: By integrating the microRNA sequencing data of human colorectal cancer from The Cancer Genome Atlas and the transcriptomic data from a small human ulcerative colitis (UC) cohort, we provisionally identify that miR-31-5p promotes the colonic inflammation-to-cancer transition. MiR-31-5p exacerbates dextran sulfate sodium-induced colitis and its transition to colitis-associated colorectal cancer (CAC) by targeting special AT-rich sequence-binding protein 2. The miR-31-5p/special AT-rich sequence-binding protein 2 axis is found to modulate Toll-like receptor-4/nuclear factor-κB and apoptosis pathways, revealing a key molecular link in UC-to-CAC transition. Resveratrol, a small plant-derived compound, ameliorates bowel inflammation and inhibits UC progression to CAC via this axis in mice in vivo. The study provides mechanistic insights into the UC-to-CAC progression and highlights the therapeutic potential of resveratrol for the diseases.