Oncofetal gene SALL4 in aggressive hepatocellular carcinoma

Kol Jia Yong, Chong Gao, Joline S J Lim, Benedict Yan, Henry Yang, Todor Dimitrov, Akira Kawasaki, Chee Wee Ong, Kwong-Fai Wong, Sanghoon Lee, Sharada Ravikumar, Supriya Srivastava, Xi Tian, Ronnie T Poon, Sheung Tat Fan, John M Luk, Yock Young Dan, Manuel Salto-Tellez, Li Chai, Daniel G Tenen

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165 Citations (Scopus)
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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-offunction 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.)
Original languageEnglish
Pages (from-to)2266-76
JournalNew England Journal of Medicine
Volume368
Issue number24
DOIs
Publication statusPublished - 13 Jun 2013

Keywords

  • Animals
  • Carcinoma, Hepatocellular
  • Metabolic Networks and Pathways
  • PTEN Phosphohydrolase
  • Humans
  • Gene Expression
  • Prognosis
  • Mice
  • Gene Expression Regulation, Neoplastic
  • Liver Neoplasms
  • Mice, Inbred Strains
  • Tumor Cells, Cultured
  • Transcription Factors
  • Adult
  • Liver
  • Transplantation, Heterologous
  • Tumor Markers, Biological

ASJC Scopus subject areas

  • Medicine(all)

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