Abstract
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.
Highlights
Primary sclerosing cholangitis (PSC) is commonly accompanied by ulcerative colitis (UC)
In PSC + UC patients, upregulation of miR-506 was accompanied by decreased levels of DNA methyltransferase 1 (DNMT1) (58% reduction vs. controls, p = 0.0001, Fig. 1b, Spearman’s rank correlation Rho: -0.31, p = 0.05, Table 1), and increased levels of phosphatase and tensin homolog (PTEN) mRNA (1.9-fold difference vs. controls, p = 0.001 (Fig. 1c)
This study showed that distinctive expressions of miR-506, targeting genes such as SPHK1, DNMT1, SPL, p53, anion exchange protein 2 (AE2), or InsP3R3, may be responsible for an increased risk of bowel cancer or severe inflammation
Summary
Primary sclerosing cholangitis (PSC) is commonly accompanied by ulcerative colitis (UC). We investigated whether miR-506 and its target genes are involved in phenotypic presentations of colonic inflammation and/or neoplasia. 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. 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. MiR-506 is a miRNA that was recently shown to directly target genes involved in various biological processes, including tumorigenesis, cell proliferation, metastasis, suppression of epithelial-to-mesenchymal transition, and immune response[5]. SPL has been reported to potentiate apoptosis via a p53-dependent pathway[13], and the loss of S1P lyase activity promotes neoplastic transformation and tumorigenesis in different cancer types[14]
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