title: Activation of IL6/IGFIR confers poor prognosis of HBV-related hepatocellular carcinoma through induction of OCT4/NANOG expression.
abstract: OBJECTIVE
  To unravel the role of interleukin (IL)-6 and insulin-like growth factor (IGF)-I receptor (IGFIR) in expressing stemness-related properties and to evaluate the prognostic values of pluripotent transcription factor OCT4/NANOG, and IGFIR in hepatocellular carcinoma (HCC).
  
  
  METHODS
  Serum levels of IL6 were detected using ELISA assays (n = 120). The effects of IL6/IGFI on stemness expression in HCC were examined using OCT4/NANOG promoter luciferase reporter, RNA interference, secondary sphere formation, side population, and xenograft animal models. The OCT4/NANOG protein and phospho-IGFI receptor (p-IGFIR) in tissues were detected by Western blotting (n = 8) and immunohistochemical staining (n = 85). OCT4, NANOG, and IGFIR expression levels in tissues (n = 191) were analyzed by real-time qRT-PCR and was correlated with early tumor recurrence using the Kaplan-Meier survival analysis.
  
  
  RESULTS
  A high positive correlation between the expression levels of OCT4/NANOG and IGFIR/p-IGFIR in human HCC tissues was observed. The concurrent expression of OCT4/NANOG/IGFIR was mostly confined to hepatitis B virus (HBV)-related HCC (HBV-HCC) and was significantly correlated with early tumor recurrence. High serum levels of IL6 were significantly correlated with high OCT4/NANOG expression. IL6 stimulated an autocrine IGFI/IGFIR expression STAT3 dependently, which stimulated stemness-related properties in both the cell lines and the xenografted mouse tumors. The inhibition of IGFIR activation by either RNA interference or by treatment with the inhibitor picropodophyllin (PPP) significantly suppressed the IL6-induced stemness-related properties both in vitro and in vivo.
  
  
  CONCLUSIONS
  The expression of pluripotency-related genes is associated with early tumor recurrence and is regulated by IL6-induced IGF/IGFIR activation, particularly in HBV-HCC.
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, College of Medicine, Taipei Medical University, Taipei, Taiwan. Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan. Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Te-Sheng
authors.initials: TS
authors.lastname: Chang
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Wu
authors.affiliation: College of Medicine, Chang Gung University, Taoyuan, Taiwan. Department of Dermatology and Centre for Evidence-Based Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Ching-Chi
authors.initials: CC
authors.lastname: Chi
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, College of Medicine, Taipei Medical University, Taipei, Taiwan. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wei-Chi
authors.initials: WC
authors.lastname: Su
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Pey-Jium
authors.initials: PJ
authors.lastname: Chang
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Kam-Fai
authors.initials: KF
authors.lastname: Lee
authors.affiliation: Department of Medical Research and Education, Cheng-Hsin General Hospital, and Faculty of Public Health, School of Medicine, Fu-Jen Catholic University, Taipei, Taiwan.
authors.forename: Tao-Hsin
authors.initials: TH
authors.lastname: Tung
authors.affiliation: School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan.
authors.forename: Jui
authors.initials: J
authors.lastname: Wang
authors.affiliation: School of Medical Laboratory Sciences and Biotechnology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Jun-Jen
authors.initials: JJ
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chiayi, Taiwan. College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Shui-Yi
authors.initials: SY
authors.lastname: Tung
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan. Department of General Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Liang-Mou
authors.initials: LM
authors.lastname: Kuo
authors.affiliation: Graduate Institute of Clinical Genomics, College of Medicine, National Taiwan University, Taipei, Taiwan. Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, National Taiwan University and Hospital, Taipei, Taiwan.
authors.forename: Hong-Nerng
authors.initials: HN
authors.lastname: Ho
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan. rita1204@tmu.edu.tw tyling@ntu.edu.tw.
authors.forename: Thai-Yen
authors.initials: TY
authors.lastname: Ling
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, College of Medicine, Taipei Medical University, Taipei, Taiwan. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan. Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei, Taiwan. Comprehensive Cancer Center of Taipei Medical University, Taipei, Taiwan. The Ph.D. Program for Translational Medicine, Taipei Medical University, Taipei, Taiwan. rita1204@tmu.edu.tw tyling@ntu.edu.tw.
authors.forename: Yen-Hua
authors.initials: YH
authors.lastname: Huang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000235:genetics* / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006515:Hepatitis B virus / Q000472:pathogenicity; D018398:Homeodomain Proteins / Q000096:biosynthesis*; D006801:Humans; D015850:Interleukin-6 / Q000097:blood*; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000097:blood / Q000235:genetics* / Q000821:virology; D051379:Mice; D000071317:Nanog Homeobox Protein; D009364:Neoplasm Recurrence, Local / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis*; D011379:Prognosis; D017451:Receptors, Somatomedin / Q000096:biosynthesis*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018398:Homeodomain Proteins; D015850:Interleukin-6; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D017451:Receptors, Somatomedin