MiR-222-3p Aggravates the Inflammatory Response by Targeting SOCS1 to Activate STAT3 Signaling in Ulcerative Colitis

Abstract

Background: Ulcerative colitis is characterized by relapsing inflammation in the gastrointestinal tract with limited treatment options. The aim of the present study was to assess the anti-inflammatory effect of Suppressor of cytokine signaling ( SOCS1 ) on lipopolysaccharide-stimulated RAW264.7 cells and to investigate its potential mechanisms. Methods: The in vitro ulcerative colitis model was established by using lipopolysaccharide-stimulated RAW264.7 cells. Western blotting was used to detect the protein expression levels of SOCS1 , JAK2 , STAT3 , and VDR . Reverse transcription-quantitative polymerase chain reaction was used to measure the mRNA expression of SOCS1 , miR-222-3p, and VDR . An enzyme-linked immunosorbent assay was performed to measure the levels of inflammatory cytokines. A luciferase assay assessed the binding of SOCS1 to miR-222-3p. A total of 15 patients with ulcerative colitis and 18 healthy controls were recruited. The expression levels of SOCS1 and miR-222-3p in the colonic mucosa tissues of patients with ulcerative colitis and healthy controls were determined by reverse transcription-quantitative polymerase chain reaction. Results: SOCS1 upregulation inhibited the lipopolysaccharide-induced inflammation in RAW264.7 cells. SOCS1 was confirmed to be targeted by miR-222-3p. Silencing SOCS1 significantly abolished the inhibitory effects of miR-222-3p downregulation on inflammation. MiR-222-3p activated STAT3 signaling and reduced VDR expression by targeting SOCS1 in lipopolysaccharide-treated RAW264.7 cells. Additionally, miR-222-3p expression was upregulated in ulcerative colitis patients ( P = 5.16E−10), while SOCS1 ( P = 2.75E−10) and VD R ( P = 52.5E−9) expression was downregulated in ulcerative colitis patients. Endoscopic scores (UCEIS) revealed significant positive correlation with miR-222-3p and negative correlation with SOCS1 and VDR . Conclusion: MiR-222-3p targets SOCS1 to aggravate the inflammatory response by suppressing VDR and activating STAT3 signaling in ulcerative colitis.

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

“…Studies have reported that miRNAs are key regulators of IEC barriers, regulating the growth and apoptosis of IECs and tight junctions between IECs (13,(45)(46)(47). There is evidence to indicate that miR-222-3p expression is upregulated in the colonic mucosal tissues of UC patients and in the colorectal tissues of CRC patients (19,20). MiR-222-3p inhibits VDR and activates STAT3 signaling pathway in RAW264.7 cells by targeting SOCS1, which in turn exacerbates inflammatory responses (19).…”

“…There is evidence to indicate that miR-222-3p expression is upregulated in the colonic mucosal tissues of UC patients and in the colorectal tissues of CRC patients (19,20). MiR-222-3p inhibits VDR and activates STAT3 signaling pathway in RAW264.7 cells by targeting SOCS1, which in turn exacerbates inflammatory responses (19). Oxidative stress has long been recognized as one of the main pathogenic factors of UC and CAC (9,48).…”

“…Among miRNAs, microRNA-222-3p (miR-222-3p) is a major regulator of oxidative stress and inhibiting the expression of miR-222-3p can significantly reduce the development of oxidative stress (17,18). Recently, there is evidence suggesting an increased in the miR-222-3p expression in the colonic mucosal tissues of UC patients and in the colorectal tissues of CRC patients (19,20). However, whether miR-222-3p plays a role in regulating oxidative stress in the colon in UC and CAC has not been investigated.…”

Role of Increased miR-222-3p Expression in Peripheral Blood and Wound Marginal Tissues of Type 2 Diabetes Mellitus Patients with Diabetic Foot Ulcer

“…21 MiR-222-3p can increase the expression of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α by targeted regulation of downstream gene functions. [25][26][27] Inflammatory cytokines, such as TNF-α and IFN-γ can also induce the upregulation of miR-222-3p expression. 15 This suggests that there may be a bidirectional regulatory effect between miR-222-3p expression and inflammatory factors, forming a vicious circle that aggravates the inflammatory response.…”