Role of miR-125b on S1P/Ceramide pathway in primary sclerosing cholangitis

The study show how the interaction of miR-125b with the sphingosine-1-phosphate (S1P)/ceramide axis may predispose patients with PSC, PSC/UC and UC to carcinogenesis in the ascending and sigmoid colon.Overexpression of miR-125b was accompanied by up-regulation of S1P, ceramide synthases, ceramide kinases and down-regulation of AT-rich interaction domain 2 in ascending colon PSC/UC. We also showed that overexpression of sphingosine kinase 2 (SPHK2) and genes involved in the glycolytic pathway in sigmoid colon UC led to increased levels of interleukin 17 (IL-17). In vitro stimulation of human intestinal epithelial cells (Caco-2, HT-29 and NCM460D) with lipopolysaccharide suppressed miR-125b and increased pro-inflammatory cytokines, while induction of miR-125b activity by miR-125b mimetic or lithocholic acid resulted in inhibition of miR-125b targets.miR-125b overexpression was associated with an imbalance in the S1P/ceramide axis, which may lead to MSI-H cancer progression in PSC/UC. Moreover, SPHK2 overexpression and altered cellular metabolic flux are important factors in inflammation-associated colorectal cancer in UC.