miR-542-5p targets c-myc and negates the cell proliferation effect of SphK1 in intestinal epithelial cells

Intestinal epithelial barrier defects occur commonly during a variety of pathological conditions, though their underlying mechanisms are not completely understood. Sphingosine-1-phosphate (S1P) has been shown to be a critical regulator of proliferation and of maintenance of an intact intestinal epithelial barrier, as is also sphingosine kinase 1 (SphK1), the rate-limiting enzyme for S1P synthesis. SphK1 has been shown to modulate its effect on intestinal epithelial proliferation through increased levels of c-myc. We conducted genome-wide profile analysis to search for differential microRNA expression related to overexpressed SphK1 demonstrating adjusted expression of microRNA 542-5p (miR-542-5p). Here, we show that miR-542-5p is regulated by SphK1 activity and is an effector of c-myc translation that ultimately serves as a critical regulator of the intestinal epithelial barrier. miR-542-5p directly regulates c-myc translation through direct binding to the c-myc mRNA. Exogenous S1P analogs administered in vivo protect murine intestinal barrier from damage due to mesenteric ischemia reperfusion, and damaged intestinal tissue had increased levels of miR-542-5p. These results indicate that miR-542-5p plays a critical role in the regulation of S1P-mediated intestinal barrier function, and may highlight a novel role in potential therapies.

Automated summary

Intestinal epithelial barrier defects commonly occur in various pathological conditions, and the underlying mechanisms are not fully understood. S1P and SphK1 are critical regulators of intestinal epithelial barrier maintenance, with miR-542-5p serving as an effector of c-myc translation. miR-542-5p directly regulates c-myc translation by binding to c-myc mRNA. This research highlights the importance of miR-542-5p in the regulation of S1P-mediated intestinal barrier function.