title: RBMY, a novel inhibitor of glycogen synthase kinase 3β, increases tumor stemness and predicts poor prognosis of hepatocellular carcinoma.
abstract: Male predominance of hepatocellular carcinoma (HCC) occurs particularly among young children aged 6-9 years, indicative of a possible role of the Y chromosome-encoded oncogene in addition to an androgenic effect. The discovery of oncogenic activation of RBMY (RNA-binding motif on Y chromosome), which is absent in normal hepatocytes but present in male HCC tissues, sheds light on this issue. Herein, we report on a critical hepatocarcinogenic role of RBMY and its ontogenic origin. During liver development, the Ser/Thr phosphorylated RBMY is expressed in the cytoplasm of human and rodent fetal livers. It is then silenced in mature hepatocytes and restricted to scarce expression in the bile ductular cells. Upon hepatocarcinogenesis, a noteworthy increase of cytoplasmic and nuclear RBMY is observed in HCC tissues; however, only the former is expressed dominantly in hepatic cancer stem cells and correlates significantly to a poor prognosis and decreased survival rate in HCC patients. Cytoplasmic expression of RBMY, which is mediated by binding to nuclear exporter chromosome region maintenance 1 and further enriched upon Wnt-3a stimulation, confers upon tumor cells the traits of cancer stem cell by augmenting self-renewal, chemoresistance, cell-cycle progression, proliferation, and xenograft tumor growth. This is achieved mechanistically through increasing Ser9 phosphorylation-inactivation of glycogen synthase kinase 3β by RBMY, thereby impeding the glycogen synthase kinase 3β-dependent degradation of β-catenin and eventually inducing the nuclear entry of β-catenin for the transcription of downstream oncogenes.
  
  
  CONCLUSIONS
  RBMY is a novel oncofetal protein that plays a key role in attenuating glycogen synthase kinase 3β activity, leading to aberrant activation of Wnt/β-catenin signaling, which facilitates malignant hepatic stemness; because of its absence from normal human tissues except the testis, RBMY represents a feasible therapeutic target for the selective eradication of HCC cells in male patients.
authors.affiliation: Department of Pediatrics.
authors.forename: Huey-Huey
authors.initials: HH
authors.lastname: Chua
authors.affiliation: Department of Pediatrics.
authors.forename: Daw-Jen
authors.initials: DJ
authors.lastname: Tsuei
authors.affiliation: Department of Surgery.
authors.forename: Po-Huang
authors.initials: PH
authors.lastname: Lee
authors.affiliation: Department of Pathology, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yung-Ming
authors.initials: YM
authors.lastname: Jeng
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Jean
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Pediatrics.
authors.forename: Jia-Feng
authors.initials: JF
authors.lastname: Wu
authors.affiliation: Department of Pediatrics.
authors.forename: De-Shiuan
authors.initials: DS
authors.lastname: Su
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chin-Sung
authors.initials: CS
authors.lastname: Chien
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Pei-Chi
authors.initials: PC
authors.lastname: Kao
authors.affiliation: Department of Obstetrics and Gynecology.
authors.forename: Chien-Nan
authors.initials: CN
authors.lastname: Lee
authors.affiliation: Department of Surgery.
authors.forename: Rey-Heng
authors.initials: RH
authors.lastname: Hu
authors.affiliation: Department of Pediatrics.|Department of Medical Genetics.
authors.forename: Yen-Hsuan
authors.initials: YH
authors.lastname: Ni
authors.affiliation: Department of Pediatrics.|Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.|Hepatitis Research Center, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Mei-Hwei
authors.initials: MH
authors.lastname: Chang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007223:Infant; D008113:Liver Neoplasms / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D049790:Nuclear Export Signals; D009687:Nuclear Proteins / Q000502:physiology*; D010766:Phosphorylation; D011379:Prognosis; D055550:Protein Stability; D016601:RNA-Binding Proteins / Q000502:physiology*; D051381:Rats; D060509:Wnt3A Protein / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism
chemical_list: D049790:Nuclear Export Signals; D009687:Nuclear Proteins; C501499:RBMY1A1 protein, human; D016601:RNA-Binding Proteins; D060509:Wnt3A Protein; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3