Silencing of miR-370 in human cholangiocarcinoma by allelic loss and interleukin-6 induced maternal to paternal epigenotype switch.

Silencing of miR-370 in human cholangiocarcinoma by allelic loss and interleukin-6 induced maternal to paternal epigenotype switch.

Blog Article

Cholangiocarcinoma (CCA) is a highly lethal malignant tumor arising from the biliary tract epithelium.Interleukin-6 (IL-6) is a major mediator of inflammation and contributor to carcinogenesis within the biliary tree.Previous studies suggested that enforced IL-6 contributes to cholangiocarcinogenesis through hypermethylation of several genes implicated in CCA.However, the precise mechanisms of IL-6 effects in CCA remain unclear.

We now demonstrate that microRNA (miR)-370 is underexpressed in Wound Care a large cohort of human CCA vs.normal liver tissues.In addition, we show that IL-6 induces a time-dependent silencing of miR-370.In addition, demethylation of CCA cells results in upregulation of miR-370.

Furthermore, we demonstrate that miR-370 is imprinted, and that the Intergenic Differentially Methylated Region (IG-DMR) responsible for imprinting regulation of this genomic locus is hypermethylated in response to IL-6 treatment.In addition, the IG-DMR is Ring Crimp Terminals hypermethylated in human CCA specimens compared to normal matched controls, in the same location as the IL-6 induced hypermethylation.Finally, miR-370 was found to regulate WNT10B in luciferase as well as western blotting experiments.Our data indicate that the paternal allele of miR-370 is normally silenced through genomic imprinting and that the overexpression of IL-6 in CCA effectively suppresses the expression of miR-370 from the maternal allele, lending support to the theory that miR-370 silencing in human CCA follows a classic two-hit mechanism.