Oncofetal gene SALL4 in aggressive hepatocellular carcinoma.


Publication Type:

Source:

N Engl J Med, Volume 368, Issue 24, p.2266-76 (2013)

Keywords:

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

Abstract:

<p><strong>BACKGROUND: </strong>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.</p>
<p><strong>METHODS: </strong>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.</p>
<p><strong>RESULTS: </strong>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.</p>
<p><strong>CONCLUSIONS: </strong>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.).</p>