Transcription factor 1 (Tcf1; hepatocyte nuclear factor 1α [HNF1α]) is critical for hepatocyte development and function. Whether Tcf1 also regulates hepatic microRNAs (miRNAs) has not been investigated yet. Here we analyzed Tcf1-dependent miRNA expression in adult mice in which this transcription factor had been genetically deleted (Tcf1(-/-) ) using miRNA microarray analysis. The miR-192/-194 cluster was markedly down-regulated in liver of Tcf1(-/-) mice. MiR-192/-194 levels were also decreased in two other tissues that 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 messenger RNAs (mRNAs) with multiple binding sites for these miRNAs. This approach revealed frizzled-6 (Fzd6) as a 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 (Dgcr8(flox/flox) p53(flox/flox) × 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.