MicroRNA-194 is a target of transcription factor 1 (Tcf1, Hnf1α) in adult liver and controls expression of frizzled-6

Transcription factor 1 (Tcf1; Hepatocyte nuclear factor 1α [Hnf1α]) is critical for hepatocyte development and function. Whether Tcf1 also regulates hepatic microRNAs (miRs) has not been investigated yet. Here, we analysed Tcf1-dependent microRNA expression in adult mice in which this transcription factor had been genetically deleted (Tcf1−/–) using microRNA microarray analysis. The miR-192/-194 cluster was markedly downregulated in liver of Tcf1−/– mice. MiR-192/-194 levels were also decreased in two other tissues, which express Tcf1, kidney and small intestine, although to a lesser extent than in liver. In order to identify targets of miR-192/-194 in vivo we combined Affymetrix gene analysis of liver in which miR-192/-194 had been silenced or overexpressed, respectively, and tested regulated mRNAs with multiple binding sites for these microRNAs. This approach revealed frizzled-6 (Fzd6) as robust endogenous target of miR-194. MiR-194 also targets human FZD6 and expression of miR-194 and Fzd6 are inversely correlated in a mouse model of hepatocellular carcinoma (Dgcr8flox/flox p53flox/flox x Alb-Cre). Conclusion: Our results support a role of miR-194 in liver tumorigenesis through its endogenous target Fzd6. These results may have important implications for Tcf1-mediated liver proliferation. (HEPATOLOGY 2011)