title: MicroRNA-194 is a target of transcription factor 1 (Tcf1, HNF1α) in adult liver and controls expression of frizzled-6.
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors: Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
authors: Jan
authors: J
authors: Krützfeldt
authors: Nora
authors: N
authors: Rösch
authors: Jean
authors: J
authors: Hausser
authors: Muthiah
authors: M
authors: Manoharan
authors: Mihaela
authors: M
authors: Zavolan
authors: Markus
authors: M
authors: Stoffel
mesh_terms: D000367:Age Factors; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D051157:Frizzled Receptors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000502:physiology; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*
chemical_list: D051157:Frizzled Receptors; C111048:Fzd6 protein, mouse; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C554845:MIRN194 microRNA, mouse; D035683:MicroRNAs; C539618:Mirn192 microRNA, mouse