By Charles Bankhead, Staff Writer, MedPage Today
Published: June 12, 2013
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco
- An oncofetal gene normally silenced in the adult liver contributes to hepatocellular carcinoma through several cellular pathways.
- Note that the findings confirmed the oncofetal gene SALL4 as a biomarker for an aggressive subtype of HCC that has a poor prognosis and suggest that SALL4 may be a potential therapeutic target in liver tumors harboring the mutated gene
An oncofetal gene normally silenced in the adult liver contributes to hepatocellular carcinoma (HCC) through several cellular pathways, investigators reported.
SALL4-positive tumor specimens overexpressed genes involved in proliferation and metastasis. Blocking the gene's protein released an inhibited tumor suppressor that prevented tumor formation in preclinical models of HCC.
The findings confirmed SALL4 as a biomarker for an aggressive subtype of HCC that has a poor prognosis and established SALL4 as a potential therapeutic target in liver tumors harboring the mutated gene, Daniel G. Tenen, MD, of the Cancer Science Institute of Singapore, and co-authors reported online in the New England Journal of Medicine.
"The absence of SALL4 expression in the healthy adult liver enhances the potential of SALL4 as a treatment target in hepatocellular carcinoma," the authors concluded.
SALL4 has a major role in the maintenance of pluripotency and self-renewal of embryonic stem cells. In preclinical models, SALL4 expression declines gradually during development and is silenced in adulthood. SALL4 has been observed in leukemia and in several types of solid tumors, including HCC.
The observation of expression of SALL4 in the murine fetal liver but not the adult liver led to the hypothesis that SALL4 plays a role in the poor-prognosis, progenitor-like subtype of HCC in adult humans.
To test their hypothesis, Tenen and colleagues compared SALL4 expression in surgically resected HCC specimens of 179 patients and archived specimens from matched patients without HCC. The investigators found that 55.6% of the HCC specimens were SALL4 positive and that the HCC specimens had a significantly higher number of SALL4-expressing cells as compared with the control liver specimens (P<0.001).
By gene-expression microarray analysis, the authors found upregulation of SALL4 in several different groups of HCC specimens. They also detected significantly different (P<0.001) levels of SALL4 expression in 228 matched HCC and non-HCC liver specimens obtained from a different institution.
The investigators analyzed SALL4 expression across 10 HCC cell lines, using polymerase chain-reaction assay techniques. The studies showed consistent expression of SALL4 but at varying levels among the different cell lines. Analysis of two nontransformed liver cell lines showed no SALL4 expression.
To examine the clinical relevance of SALL4 reactivation in HCC, Tenen and colleagues performed clinicopathologic analyses of two independent HCC specimen sets. They found that higher SALL4 expression was associated with worse prognosis, including worse survival, in both sets of specimens (P=0.02 to P=0.002). SALL4-positive HCCs had a gene-expression profile associated with poorly differentiated, aggressive tumors that have a poor prognosis.
Additional studies showed that SALL4 expression had no association with baseline liver function or with the presence or absence of lymph node metastasis.
The authors assessed the importance of SALL4 to HCC by performing SALL4-knock down studies. The resulting loss of function was associated with decreased cell viability, increased apoptosis, and decreased tumorigenicity in HCC cells.
Results of the loss-of-function studies suggested that SALL4 is a potential therapeutic target in HCC. They tested a recently described peptide that blocks interaction between SALL4 and a histone deacetylase-containing nucleosome remodeling and HDAC (NuRD) complex, an interaction necessary for SALL4 to function as a transcription repressor.
The studies showed that the SALL4 peptide decreased viability of SALL4-positive HCC cells by induction of PTEN and that the effect was reversed by a PTEN inhibitor.
"The discovery of a role for SALL4 in hepatocellular carcinoma, its association with prognosis, and the antitumor effects of a newly identified peptide blocker targeting it have potential therapeutic significances," the authors said. "Testing for the presence of SALL4 at diagnosis may be helpful not only for determining the prognosis but also for identifying patients who are likely to have a response to treatment."
The study contributed important new information to the origin and potential treatment of aggressive HCC, according to the authors of an accompanying editorial. However, some questions remain.
"Although these data are convincing, it is not known whether targeting of SALL4 alone would have sufficient antitumor activity or whether inhibition of the associated transcriptomic programs is required to prevent recurrent disease," said Jens U. Marquardt, MD, of the National Cancer Institute, and Snorri S. Thorgeirsson, MD, PhD, of Johannes Gutenberg University in Mainz, Germany.
"Another open question is whether responses to SALL4 inhibition in stemness-associated tumors vary according to the patient's ethnic origin and the cause of hepatocellular carcinoma. This variability has been repeatedly observed in other targeted therapies. Also, the present data do not resolve whether tumors that overexpress SALL4 are derived from reprogrammed hepatocytes or rare stem cells."
An urgent need exists for clinical translation of the findings to guide individualized therapy for HCC and to improve the poor outcome associated with the disease, they added.
The study was supported by the Singapore National Medical Research Council, the Singapore Ministry of Education and the National Research Foundation, and the National Institutes of Health.
Tenen reported no relevant disclosures. One or more co-authors disclosed relationships with sanofi-aventis and Merck.
Primary source: New England Journal of Medicine
Yong KJ, et al "Oncofetal gene SALL4 in aggressive hepatocellular carcinoma" N Engl J Med 2013; DOI: 10.1056/NEJMoa1300297.
Additional source: New England Journal of Medicine
Marquardt JU, Thorgeirsson SS "SALL4 in 'stemness'-driven hepatocarcinogenesis" N Engl J Med 2013; DOI: 10.1056/NEJMe1303026.