Oncofetal gene SALL4 in aggressive hepatocellular carcinoma

N Engl J Med. 2013 Jun 13;368(24):2266-76. doi: 10.1056/NEJMoa1300297.

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.).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Biomarkers, Tumor / metabolism*
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism*
  • Gene Expression
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Liver / metabolism*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Metabolic Networks and Pathways / physiology
  • Mice
  • Mice, Inbred Strains
  • PTEN Phosphohydrolase / metabolism
  • Prognosis
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transplantation, Heterologous
  • Tumor Cells, Cultured

Substances

  • Biomarkers, Tumor
  • SALL4 protein, human
  • Transcription Factors
  • PTEN Phosphohydrolase
  • PTEN protein, human