title: Arsenic trioxide induces differentiation of CD133+ hepatocellular carcinoma cells and prolongs posthepatectomy survival by targeting GLI1 expression in a mouse model.
abstract: BACKGROUND
  Cancer stem cells (CSCs) play a key role in the posthepatectomy recurrence of hepatocellular carcinoma (HCC). CD133+ HCC cells exhibit liver CSC-like properties, and CSC differentiation-inducing therapy may lead these cells to lose their self-renewal ability and may induce terminal differentiation, which may in turn allow their malignant potential to be controlled. Because arsenic trioxide (As₂O₃) increases remission rates and prolongs survival among patients with acute promyelocytic leukemia by inducing differentiation and apoptosis of leukemic cells, we hypothesized that As₂O₃ might also inhibit HCC recurrence and prolong survival time after hepatectomy by inducing differentiation of HCC CSCs.
  
  
  METHODS
  We evaluated the As₂O₃ induced differentiation of human HCC CSCs and its mechanism in vitro, and we investigated the effects of treatment with As₂O₃ on recurrence rates and median survival in a mouse xenograft model.
  
  
  RESULTS
  We found that As₂O₃ induced HCC CSC differentiation by down-regulating the expression of CD133 and some stemness genes, thus inhibiting the cells' self-renewal ability and tumorigenic capacity without inhibiting their proliferation in vitro. In vivo experiments indicated that As₂O₃ decreased recurrence rates after radical resection and prolonged survival in a mouse model. As₂O₃, which shows no apparent toxicity, may induce HCC CSC differentiation by down-regulating the expression of GLI1.
  
  
  CONCLUSIONS
  We found that As₂O₃ induced HCC CSC differentiation, inhibited recurrence, and prolonged survival after hepatectomy by targeting GLI1expression. Our results suggest that the clinical safety and utility of As₂O₃ should be further evaluated.
authors.forename: Ke-Zhi
authors.initials: KZ
authors.lastname: Zhang
authors.forename: Qiang-Bo
authors.initials: QB
authors.lastname: Zhang
authors.forename: Quan-Bao
authors.initials: QB
authors.lastname: Zhang
authors.forename: Hui-Chuan
authors.initials: HC
authors.lastname: Sun
authors.forename: Jian-Yang
authors.initials: JY
authors.lastname: Ao
authors.forename: Zong-Tao
authors.initials: ZT
authors.lastname: Chai
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhu
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Bu
authors.forename: Ling-Qun
authors.initials: LQ
authors.lastname: Kong
authors.affiliation: Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory for Carcinogenesis and Cancer Invasion, The Chinese Ministry of Education, 136 Yi Xue Yuan Road, Shanghai 200032, P R China. zytang88@163.com.
authors.forename: Zhao-You
authors.initials: ZY
authors.lastname: Tang
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015536:Down-Regulation; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000473:pathology; D010087:Oxides / Q000494:pharmacology*; D010455:Peptides / Q000378:metabolism*; D011897:Random Allocation; D015398:Signal Transduction; D016019:Survival Analysis; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000071676:Zinc Finger Protein GLI1
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D001152:Arsenicals; C400551:GLI1 protein, human; D006023:Glycoproteins; D010087:Oxides; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000077237:Arsenic Trioxide