title: Oncofetal gene SALL4 in aggressive hepatocellular carcinoma.
abstract: BACKGROUND
  Hepatocellular carcinoma is the third leading cause of cancer-related deaths worldwide. In the heterogeneous group of hepatocellular carcinomas, those with characteristics of embryonic stem-cell and progenitor-cell gene expression are associated with the worst prognosis. The oncofetal gene SALL4, a marker of a subtype of hepatocellular carcinoma with progenitor-like features, is associated with a poor prognosis and is a potential target for treatment.
  
  
  METHODS
  We screened specimens obtained from patients with primary hepatocellular carcinoma for the expression of SALL4 and carried out a clinicopathological analysis. Loss-of-function studies were then performed to evaluate the role of SALL4 in hepatocarcinogenesis and its potential as a molecular target for therapy. To assess the therapeutic effects of a peptide that targets SALL4, we used in vitro functional and in vivo xenograft assays.
  
  
  RESULTS
  SALL4 is an oncofetal protein that is expressed in the human fetal liver and silenced in the adult liver, but it is reexpressed in a subgroup of patients who have hepatocellular carcinoma and an unfavorable prognosis. Gene-expression analysis showed the enrichment of progenitor-like gene signatures with overexpression of proliferative and metastatic genes in SALL4-positive hepatocellular carcinomas. Loss-of-function studies confirmed the critical role of SALL4 in cell survival and tumorigenicity. Blocking SALL4-corepressor interactions released suppression of PTEN (the phosphatase and tensin homologue protein) and inhibited tumor formation in xenograft models in vivo.
  
  
  CONCLUSIONS
  SALL4 is a marker for a progenitor subclass of hepatocellular carcinoma with an aggressive phenotype. The absence of SALL4 expression in the healthy adult liver enhances the potential of SALL4 as a treatment target in hepatocellular carcinoma. (Funded by the Singapore National Medical Research Council and others.).
authors.affiliation: Cancer Science Institute of Singapore, the National University of Singapore Graduate School for Integrative Sciences and Engineering, Singapore.
authors.forename: Kol Jia
authors.initials: KJ
authors.lastname: Yong
authors.forename: Chong
authors.initials: C
authors.lastname: Gao
authors.forename: Joline S J
authors.initials: JS
authors.lastname: Lim
authors.forename: Benedict
authors.initials: B
authors.lastname: Yan
authors.forename: Henry
authors.initials: H
authors.lastname: Yang
authors.forename: Todor
authors.initials: T
authors.lastname: Dimitrov
authors.forename: Akira
authors.initials: A
authors.lastname: Kawasaki
authors.forename: Chee Wee
authors.initials: CW
authors.lastname: Ong
authors.forename: Kwong-Fai
authors.initials: KF
authors.lastname: Wong
authors.forename: Sanghoon
authors.initials: S
authors.lastname: Lee
authors.forename: Sharada
authors.initials: S
authors.lastname: Ravikumar
authors.forename: Supriya
authors.initials: S
authors.lastname: Srivastava
authors.forename: Xi
authors.initials: X
authors.lastname: Tian
authors.forename: Ronnie T
authors.initials: RT
authors.lastname: Poon
authors.forename: Sheung Tat
authors.initials: ST
authors.lastname: Fan
authors.forename: John M
authors.initials: JM
authors.lastname: Luk
authors.forename: Yock Young
authors.initials: YY
authors.lastname: Dan
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
authors.forename: Li
authors.initials: L
authors.lastname: Chai
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
mesh_terms: D000328:Adult; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D053858:Metabolic Networks and Pathways / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011379:Prognosis; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; C472575:SALL4 protein, human; D014157:Transcription Factors; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human