Department of Medical Biology, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland.
Liver and Internal Medicine Unit, Medical University of Warsaw, 02-097 Warsaw, Poland.
Int J Mol Sci. 2022 Apr 28;23(9):4905. doi: 10.3390/ijms23094905.
Deficient mismatch repair (MMR) proteins may lead to DNA damage and microsatellite instability. Primary sclerosing cholangitis (PSC) is a risk factor for colitis-associated colon cancer. MiR-155 is suggested to act as a key regulating node, linking inflammation and tumorigenesis. However, its involvement in the chronic colitis of PSC-UC patients has not been examined. We investigated the involvement of miR-155 in the dysregulation of MMR genes and colitis in PSC patients. Colon tissue biopsies were obtained from patients with PSC, PSC with concomitant ulcerative colitis (PSC-UC), uncomplicated UC, and healthy controls ( = 10 per group). In the ascending colon of PSC and PSC-UC patients, upregulated miR-155 promoted high microsatellite instability and induced signal transducer and activator of transcription 3 (STAT-3) expression via the inhibition of suppressors of cytokine signalling 1 (SOCS1). In contrast, the absence of miR-155 overexpression in the sigmoid colon of PSC-UC patients activated the Il-6/S1PR1 signalling pathway and imbalanced the IL17/FOXP3 ratio, which reinforces chronic colitis. Functional studies on human intestinal epithelial cells (HT-29 and NCM460D) confirmed the role of miR-155 over-expression in the inhibition of MMR genes and the modulation of p53. Moreover, those cells produced more TNFα upon a lipopolysaccharide challenge, which led to the suppression of miR-155. Additionally, exposure to bile acids induced upregulation of miR-155 in Caco-2 cell lines. Thus, under different conditions, miR-155 is involved in either neoplastic transformation in the ascending colon or chronic colitis in the sigmoid colon of patients with PSC. New insight into local modulation of microRNAs, that may alter the course of the disease, could be used for further research on potential therapeutic applications.
错配修复（MMR）蛋白缺陷可能导致 DNA 损伤和微卫星不稳定。原发性硬化性胆管炎（PSC）是结肠炎相关结肠癌的危险因素。miR-155 被认为是连接炎症和肿瘤发生的关键调节节点。然而，其在 PSC-UC 患者慢性结肠炎中的作用尚未得到研究。我们研究了 miR-155 在 PSC 患者 MMR 基因失调和结肠炎中的作用。从 PSC 患者、PSC 合并溃疡性结肠炎（PSC-UC）患者、单纯性溃疡性结肠炎患者和健康对照者（每组 10 例）获得结肠组织活检。在 PSC 和 PSC-UC 患者的升结肠中，上调的 miR-155 通过抑制细胞因子信号转导抑制因子 1（SOCS1）促进高微卫星不稳定性，并诱导信号转导和转录激活因子 3（STAT-3）表达。相反，在 PSC-UC 患者的乙状结肠中缺乏 miR-155 过表达激活了白细胞介素 6/鞘氨醇 1 受体 1（S1PR1）信号通路，并使 IL17/FOXP3 比值失衡，从而加重慢性结肠炎。对人肠上皮细胞（HT-29 和 NCM460D）的功能研究证实了 miR-155 过表达在抑制 MMR 基因和调节 p53 中的作用。此外，这些细胞在脂多糖刺激下产生更多的 TNFα，从而抑制 miR-155。此外，暴露于胆盐会诱导 Caco-2 细胞系中 miR-155 的上调。因此，在不同条件下，miR-155 参与 PSC 患者升结肠中的肿瘤转化或乙状结肠中的慢性结肠炎。对微 RNA 局部调节的新认识，可能会改变疾病的进程，可用于进一步研究潜在的治疗应用。
