title: Wilms' tumor 1 gene modulates Fas-related death signals and anti-apoptotic functions in hepatocellular carcinoma.
abstract: BACKGROUND
  The Wilms' tumor 1 (WT1) gene is known to be overexpressed in hepatocellular carcinoma (HCC) and to upregulate tumor growth and oncogenic potential, although the detailed mechanisms remain to be elucidated.
  
  
  METHODS
  We identified host genes involved in WT1 gene modulation of human liver cancer cell lines in vitro, and further characterized genes related to apoptosis. Moreover, we evaluated the alteration of genes by WT1 in 40 HCC and 58 non-HCC human liver samples collected at resection.
  
  
  RESULTS
  Analysis of the effect of small interfering RNAs-mediated knock-down of WT1 on apoptosis using an annexin V labeling assay, and on modulation of the activity of caspases-3, -8 and -9, indicated that WT1 has an anti-apoptotic role. We identified three apoptosis-related genes that were modulated by WT1; the cellular FLICE-inhibitory proteins (cFLIP) gene was upregulated, and Fas-associated death domain (FADD) and nuclear factor kappa B (NF-κB) were downregulated. Interestingly, knock-down of FADD or NF-κB resulted in the upregulation of WT1, and the expression of cFLIP changed in parallel with WT1 expression. We further evaluated WT1-mediated alteration of genes in HCC and non-HCC human liver samples. Both HCC and non-HCC tissues that expressed relatively high levels of WT1 showed cFLIP overexpression.
  
  
  CONCLUSIONS
  WT1 modulates cFLIP, FADD and NF-κB, and has an anti-apoptotic role in HCC. This mechanism of action of WT1 could be related to the tumor growth and oncogenic potential of HCC.
authors.affiliation: Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Uesugi
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Hiasa
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Tokumoto
authors.forename: Toshie
authors.initials: T
authors.lastname: Mashiba
authors.forename: Yohei
authors.initials: Y
authors.lastname: Koizumi
authors.forename: Masashi
authors.initials: M
authors.lastname: Hirooka
authors.forename: Masanori
authors.initials: M
authors.lastname: Abe
authors.forename: Bunzo
authors.initials: B
authors.lastname: Matsuura
authors.forename: Morikazu
authors.initials: M
authors.lastname: Onji
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000235:genetics; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000096:biosynthesis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D052138:Genes, Neoplasm; D016162:Genes, Wilms Tumor / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D014407:Tumor Cells, Cultured; D025721:WT1 Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053200:Fas-Associated Death Domain Protein; D016328:NF-kappa B; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D025721:WT1 Proteins