title: Octamer 4/microRNA-1246 signaling axis drives Wnt/β-catenin activation in liver cancer stem cells.
abstract: Wnt/β-catenin signaling is activated in CD133 liver cancer stem cells (CSCs), a subset of cells known to be a root of tumor recurrence and therapy resistance in hepatocellular carcinoma (HCC). However, the regulatory mechanism of this pathway in CSCs remains unclear. Here, we show that human microRNA (miRNA), miR-1246, promotes cancer stemness, including self-renewal, drug resistance, tumorigencity, and metastasis, by activation of the Wnt/β-catenin pathway through suppressing the expression of AXIN2 and glycogen synthase kinase 3β (GSK3β), two key members of the β-catenin destruction complex. Clinically, high endogenous and circulating miR-1246 was identified in HCC clinical samples and correlated with a worse prognosis. Further functional analysis identified octamer 4 (Oct4) to be the direct upstream regulator of miR-1246, which cooperatively drive β-catenin activation in liver CSCs.
  
  
  
  These findings uncover the noncanonical regulation of Wnt/β-catenin in liver CSCs by the Oct4/miR-1246 signaling axis, and also provide a novel diagnostic marker as well as therapeutic intervention for HCC. (Hepatology 2016;64:2062-2076).
authors.affiliation: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Stella
authors.initials: S
authors.lastname: Chai
authors.affiliation: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Kai-Yu
authors.initials: KY
authors.lastname: Ng
authors.affiliation: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Man
authors.initials: M
authors.lastname: Tong
authors.affiliation: Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong.
authors.forename: Eunice Y
authors.initials: EY
authors.lastname: Lau
authors.affiliation: Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong.
authors.forename: Terence K
authors.initials: TK
authors.lastname: Lee
authors.affiliation: Departments of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Kwok Wah
authors.initials: KW
authors.lastname: Chan
authors.affiliation: State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Yuan
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Tan-To
authors.initials: TT
authors.lastname: Cheung
authors.affiliation: Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Siu-Tim
authors.initials: ST
authors.lastname: Cheung
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Xiao-Qi
authors.initials: XQ
authors.lastname: Wang
authors.affiliation: Department of Anatomical and Cellular Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Wong
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.|State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Chung-Mau
authors.initials: CM
authors.lastname: Lo
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.|State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Kwan
authors.initials: K
authors.lastname: Man
authors.affiliation: Department of Clincial Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.|State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Xin-Yuan
authors.identifier: 0000-0002-4485-6017
authors.initials: XY
authors.lastname: Guan
authors.affiliation: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.|State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ma
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000503:physiopathology*; D006801:Humans; D008113:Liver Neoplasms / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000502:physiology*; D014411:Neoplastic Stem Cells; D050814:Octamer Transcription Factor-3 / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology*
chemical_list: C577700:MIRN1246 microRNA, human; D035683:MicroRNAs; D050814:Octamer Transcription Factor-3; D051176:beta Catenin