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.
|SALL4 is an oncofetal protein that is expressed in the human fetal liver |
|New England Journal of Medicine|
Dr Kol Jia Yong and colleagues 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.
The research team assessed the therapeutic effects of a peptide that targets SALL4, and used in vitro functional and in vivo xenograft assays.
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.
The team used gene-expression analysis to show 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, and inhibited tumor formation in xenograft models in vivo.
Dr Yong's team concludes, "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."