Suppression of microRNA-222-3p ameliorates ulcerative colitis and colitis-associated colorectal cancer to protect against oxidative stress via targeting BRG1 to activate Nrf2/HO-1 signaling pathway

Abstract

Oxidative stress is an important pathogenic factor in ulcerative colitis (UC) and colitis-associated colorectal cancer (CAC), further impairing the entire colon. Intestinal epithelial cells (IECs) are crucial components of innate immunity and play an important role in maintaining intestinal barrier function. Recent studies have indicated that microRNA-222-3p (miR-222-3p) is increased in colon of UC and colorectal cancer (CRC) patients, and miR-222-3p is a crucial regulator of oxidative stress. However, whether miR-222-3p influences IEC oxidative stress in UC and CAC remains unknown. This study investigated the effect of miR-222-3p on the regulation of IEC oxidative stress in UC and CAC. An in vitro inflammation model was established in NCM460 colonic cells, mouse UC and CAC models were established in vivo, and IECs were isolated. The biological role and mechanism of miR-222-3p-mediated oxidative stress in UC and CAC were determined. We demonstrated that miR-222-3p expression was notably increased in dextran sulfate sodium (DSS)-induced NCM460 cells and IECs from UC and CAC mice. In vitro, these results showed that the downregulation of miR-222-3p reduced oxidative stress, caspase-3 activity, IL-1β and TNF-α in DSS-induced NCM460 cells. We further identified BRG1 as the target gene of miR-222-3p, and downregulating miR-222-3p alleviated DSS-induced oxidative injury via promoting BRG1-mediated activation Nrf2/HO-1 signaling in NCM460 cells. The in vivo results demonstrated that inhibiting miR-222-3p in IECs significantly relieved oxidative stress and inflammation in the damaged colons of UC and CAC mice, as evidenced by decreases in ROS, MDA, IL-1β and TNF-α levels and increases in GSH-Px levels. Our study further demonstrated that inhibiting miR-222-3p in IECs attenuated oxidative damage by targeting BRG1 to activate the Nrf2/HO-1 signaling. In summary, inhibiting miR-222-3p in IECs attenuates oxidative stress by targeting BRG1 to activate the Nrf2/HO-1 signaling, thereby reducing colonic inflammation and tumorigenesis.

Research advancements and perspectives of inflammatory bowel disease: A comprehensive review

“…Targeting specific lncRNAs and miRNAs for silencing or overexpression provides therapeutic benefits, such as the inhibition of miR-222-3p for relieving DSS-induced damage of the colon. 139 Another approach is to utilize lncRNAs and miRNAs as potential therapeutic agents to target the relevant pathogenic factors. A noteworthy example of this is theaflavin 3-gallate, a natural compound mimicking lncRNA Gm31629.…”

Role played by MDSC in colitis-associated colorectal cancer and potential therapeutic strategies

“…MDSC infiltration is often seen at sites of inflammation in patients with chronic inflammatory diseases and tumor, relevant studies have shown that certain pro-inflammatory mediators present in the microenvironment, like IL-6, contribute to the promotion of MDSC accumulation in the pathological state of chronic inflammation and malignancy (Laws et al 2023 ). Prostaglandin E2 (PGE2) is a significant lipid mediator that produced in the sustained inflammatory response, also further recruits MDSC, which in chronic inflammation further produce S100A8/A9 proteins, these calcium-binding proteins are mainly secreted by neutrophils and activated monocytes, and interestingly, these proteins in the inflammatory microenvironment in the inflammatory microenvironment further recruiting more MDSC causing further MDSC accumulation, the inflammatory microenvironment can also further increase the generation of reactive oxygen species (ROS) and pro-angiogenic factors like vascular endothelial growth factor (VEGF), which can contribute to MDSC accumulation and immunosuppressive activity, in addition, the tumor microenvironment and persistent inflammatory stimuli can also lead to an additional boost in the production of tumor necrosis factor alpha (TNF-α) by tumor cells, which also further recruits MDSC and enhances MDSC-associated immunosuppressive activity (Wang et al 2023a , b , c , d , e ). Multiple research studies have consistently shown that reducing MDSCs can effectively slow down tumor progression and lead to anti-tumor effects, and all these evidences suggest that MDSCs play unique and crucial roles in the progression of inflammatory bowel disease to CAC development (Krishnamoorthy et al 2021 ; Liao et al 2019 ; Wang et al 2023e ).…”

“…Additionally, STAT3 was found to increase the expression of S100A8/9 proteins, which promotes the clustering of MDSCs in the tumor microenvironment (TME). This clustering ultimately leads to the activation and multiplication of MDSCs (Wang et al 2023a , b , c , d , e ). Using single-cell cytokine profiling for immunoassay, G. Qin et al found that MDSCs were significantly expressed in both clinical samples and mouse models of tumors, Additionally, they observed that specific factors like GM-CSF, G-CSF, IL-6, VEGF, etc., amplified the quantity of MDSCs in the tumor microenvironment and impeded their subsequent differentiation, and these factors further activated the JAK/STAT signaling pathway to stimulate myeloid cell production and promote MDSC expansion (Qin et al 2023 ).…”

“…It has the ability to activate Janus kinase (JAK) and induce phosphorylation of the transcription factor STAT3 downstream, thus promoting the development of cancer. Apart from the JAK/STAT3 pathway, IL-6 can also exacerbate the intestinal inflammatory response in patients and promote colitis-associated colorectal cancer by regulation of Th17 and Treg cell proliferation and function (Wang et al 2023a , b , c , d , e ). IL-6 produced by MDSCs can hinder the development and activity of CD4( +) T cells, ultimately promoting tumor development (Tsukamoto et al 2013 ).…”

Knockdown of TOP2A suppresses IL‐17 signaling pathway and alleviates the progression of ulcerative colitis

“…SLC6A14 promotes ferroptosis of epithelial cells through the C/EBPβ‐PAK6 axis of UC 5 . Inhibition of miR‐222‐3p reduces oxidative damage to activate Nrf2/HO‐1 signaling by targeting BRG1, thereby improving UC and colorectal cancer 6 . ACSF2 can mediate ferroptosis to participate in the progression of UC 7 .…”