Department of Medical Biology, Pomeranian Medical University, 70-111, Szczecin, Poland.
Liver and Internal Medicine Unit, Medical University of Warsaw, 02-097, Warsaw, Poland.
Sci Rep. 2021 May 12;11(1):10134. doi: 10.1038/s41598-021-89631-4.
Primary sclerosing cholangitis (PSC) is commonly accompanied by ulcerative colitis (UC). MicroRNA-506 modulates expression of genes which are essential for sphingosine-mediated signaling pathway and intestinal mucosa protection. We investigated whether miR-506 and its target genes are involved in phenotypic presentations of colonic inflammation and/or neoplasia. We analyzed serum and colon tissue samples collected from patients with PSC, PSC with concurrent UC (PSC + UC), UC alone, and healthy controls (n = 10 each). MiR-506 was substantially upregulated in ascending colons of PSC and PSC + UC patients, in contrast to sigmoid colons of PSC and UC patients. Upregulation of miR-506 was associated with inhibition of SPHK1, AE2, InsP3R3, and p53. Colonic suppression of miR-506 presented in UC was accompanied by substantially increased DNMT1, SPHK1, and S1P lyase expressions. A functional in vitro analysis in Caco-2 cells showed that the induction of miR-506 activity by miR-506 mimic or GDCDA bile acid suppressed, whereas inhibition of miR-506 by miR-506 inhibitor or lipopolysaccharide (LPS) upregulated the expression of the examined target genes. A different phenotypic presentation of colitis may be related to miR-506 expression. In ascending colons with PSC + UC, upregulation of miR-506 may result in failure of bicarbonate secretion and inhibition of p53, which predisposes to pro-tumorigenic transformation. In contrast, downregulation of miR-506 enhances S1P production, leading to pro-inflammatory signaling.
原发性硬化性胆管炎（PSC）通常伴有溃疡性结肠炎（UC）。microRNA-506 调节参与鞘氨醇介导的信号通路和肠黏膜保护的基因表达。我们研究了 miR-506 及其靶基因是否参与结肠炎症和/或肿瘤的表型表现。我们分析了来自 PSC 患者、PSC 合并 UC（PSC+UC）患者、UC 患者和健康对照者（每组各 10 例）的血清和结肠组织样本。与 PSC 和 UC 患者的乙状结肠相比，PSC 和 PSC+UC 患者的升结肠中 miR-506 显著上调。miR-506 的上调与 SPHK1、AE2、InsP3R3 和 p53 的抑制有关。UC 中 colonic 抑制 miR-506 与 DNMT1、SPHK1 和 S1P 裂合酶表达显著增加有关。在 Caco-2 细胞中的功能体外分析表明，miR-506 模拟物或 GDCDA 胆汁酸诱导 miR-506 活性，而 miR-506 抑制剂或脂多糖（LPS）抑制 miR-506 上调了所检查的靶基因的表达。结肠炎的不同表型表现可能与 miR-506 表达有关。在 PSC+UC 的升结肠中，miR-506 的上调可能导致碳酸氢盐分泌失败和 p53 抑制，从而导致促肿瘤转化。相比之下，miR-506 的下调增强了 S1P 的产生，导致促炎信号。
