title: MicroRNA122 is a key regulator of α-fetoprotein expression and influences the aggressiveness of hepatocellular carcinoma.
abstract: α-fetoprotein (AFP) is not only a widely used biomarker in hepatocellular carcinoma (HCC) surveillance, but is also clinically recognized as linked with aggressive tumour behaviour. Here we show that deregulation of microRNA122, a liver-specific microRNA, is a cause of both AFP elevation and a more biologically aggressive phenotype in HCC. We identify CUX1, a direct target of microRNA122, as a common central mediator of these two effects. Using liver tissues from transgenic mice in which microRNA122 is functionally silenced, an orthotopic xenograft tumour model, and human clinical samples, we further demonstrate that a microRNA122/CUX1/microRNA214/ZBTB20 pathway regulates AFP expression. We also show that the microRNA122/CUX1/RhoA pathway regulates the aggressive characteristics of tumours. We conclude that microRNA122 and associated signalling proteins may represent viable therapeutic targets, and that serum AFP levels in HCC patients may be a surrogate marker for deregulated intracellular microRNA122 signalling pathways in HCC tissues.
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kojima
authors.forename: Akemi
authors.initials: A
authors.lastname: Takata
authors.forename: Charles
authors.initials: C
authors.lastname: Vadnais
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Otsuka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Masao
authors.initials: M
authors.lastname: Akanuma
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kondo
authors.forename: Young Jun
authors.initials: YJ
authors.lastname: Kang
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kishikawa
authors.forename: Naoya
authors.initials: N
authors.lastname: Kato
authors.forename: Zhifang
authors.initials: Z
authors.lastname: Xie
authors.forename: Weiping J
authors.initials: WJ
authors.lastname: Zhang
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Yoshida
authors.forename: Masao
authors.initials: M
authors.lastname: Omata
authors.forename: Alain
authors.initials: A
authors.lastname: Nepveu
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D008113:Liver Neoplasms / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism; D000509:alpha-Fetoproteins / Q000378:metabolism*
chemical_list: C000624101:Cux1 protein, mouse; D017931:DNA Primers; D018398:Homeodomain Proteins; D035683:MicroRNAs; C544354:Mirn122 microRNA, mouse; C534781:Mirn214 microRNA, mouse; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C520426:Zbtb20 protein, mouse; D000509:alpha-Fetoproteins