title: Signal transducer and activator of transcription 3-mediated CD133 up-regulation contributes to promotion of hepatocellular carcinoma.
abstract: Enhanced expression of the cancer stem cell (CSC) marker, CD133, is closely associated with a higher rate of tumor formation and poor prognosis in hepatocellular carcinoma (HCC) patients. Despite its clinical significance, the molecular mechanism underlying the deregulation of CD133 during tumor progression remains to be clarified. Here, we report on a novel mechanism by which interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling up-regulates expression of CD133 and promotes HCC progression. STAT3 activated by IL-6 rapidly bound to CD133 promoter and increased protein levels of CD133 in HCC cells. Reversely, in hypoxic conditions, RNA interference silencing of STAT3 resulted in decrease of CD133 levels, even in the presence of IL-6, with a concomitant decrease of hypoxia-inducible factor 1 alpha (HIF-1α) expression. Active STAT3 interacted with nuclear factor kappa B (NF-κB) p65 subunit to positively regulate the transcription of HIF-1α providing a mechanistic explanation on how those three oncogenes work together to increase the activity of CD133 in a hypoxic liver microenvironment. Activation of STAT3 and its consequent induction of HIF-1α and CD133 expression were not observed in Toll-like receptor 4/IL-6 double-knockout mice. Long-term silencing of CD133 by a lentiviral-based approach inhibited cancer cell-cycle progression and suppressed in vivo tumorigenicity by down-regulating expression of cytokinesis-related genes, such as TACC1, ACF7, and CKAP5. We also found that sorafenib and STAT3 inhibitor nifuroxazide inhibit HCC xenograft formation by blocking activation of STAT3 and expression of CD133 and HIF-1α proteins.
  
  
  CONCLUSIONS
  IL-6/STAT3 signaling induces expression of CD133 through functional cooperation with NF-κB and HIF-1α during liver carcinogenesis. Targeting STAT3-mediated CD133 up-regulation may represent a novel, effective treatment by eradicating the liver tumor microenvironment.
authors.affiliation: Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.|Neuro-Immune Information Storage Network Research Center, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Cheolhee
authors.initials: C
authors.lastname: Won
authors.affiliation: Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.|Biomedical Science Project (BK21PLUS), Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Byung-Hak
authors.initials: BH
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Yi
authors.affiliation: Department of Radiation Oncology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Kyung-Ju
authors.initials: KJ
authors.lastname: Choi
authors.affiliation: Department of Pharmacology, Pusan National University School of Medicine, Yangsan, South Korea.
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Kim
authors.affiliation: Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Jeong
authors.affiliation: Laboratory of Molecular Oncology, Cheil General Hospital and Women's Healthcare Center, Kwandong University College of Medicine, Seoul, South Korea.
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Ja-June
authors.initials: JJ
authors.lastname: Jang
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Jung-Hwan
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
authors.forename: Won-Il
authors.initials: WI
authors.lastname: Jeong
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul, South Korea.
authors.forename: In-Chul
authors.initials: IC
authors.lastname: Park
authors.affiliation: Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, South Korea.
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Pusan National University School of Medicine, Yangsan, South Korea.
authors.forename: Sun Sik
authors.initials: SS
authors.lastname: Bae
authors.affiliation: Laboratory of Experimental Carcinogenesis, The Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Valentina M
authors.initials: VM
authors.lastname: Factor
authors.affiliation: Department of Anatomy, State Key Laboratory for Liver Research, Faculty of Medicine, The University of Hong Kong, Hong Kong.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ma
authors.affiliation: Laboratory of Experimental Carcinogenesis, The Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Snorri S
authors.initials: SS
authors.lastname: Thorgeirsson
authors.affiliation: Department of Radiation Oncology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Yun-Han
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.|Neuro-Immune Information Storage Network Research Center, Seoul National University College of Medicine, Seoul, South Korea.|Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Sang-Kyu
authors.initials: SK
authors.lastname: Ye
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000209:etiology*; D015687:Cell Hypoxia; D006023:Glycoproteins / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D008113:Liver Neoplasms / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; D015850:Interleukin-6; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D050796:STAT3 Transcription Factor