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Characteristics of hepatocellular carcinoma with stem/progenitor cell phenotypes.

Liver cancers are the third leading cause of cancer mortality worldwide. Among primary liver cancers, hepatocellular carcinoma (HCC) is the most common histologic subtype, accounting for 70%–85% of the total liver cancer globally. The molecular mechanisms underlying hepatocarcinogenesis, however, remain unclear. Radiofrequency ablation, surgical resection, and liver transplantation could be curative for qualified patients with early HCC, but the prognosis is poor for patients with advanced HCC. Further studies of the mechanisms underlying hepatocarcinogenesis and the development of more effective therapies are needed to improve the prognosis. In their study published in The New England Journal of Medicine, Yong et al investigated the role of the oncofetal gene SALL4 in HCC based on the following previous findings: (1) SALL4 is a key factor for maintaining pluripotency and self-renewal in embryonic stem cells; (2) in mice, SALL4 is expressed in fetal liver, but disappears by adulthood (Gastroenterology 2009;108:2726–2735); (3) SALL4 expression is detectable in various human tumors; and (4) a progenitor-like subtype of HCC is reported to be associated with poor prognosis. The authors thus hypothesized that SALL4 could be a marker of an HCC subtype with progenitor-like properties and thus a worse prognosis. First, they examined SALL4 expression in human liver tissues, and confirmed that SALL4 was expressed in fetal liver, but not in adult liver, and reexpressed in a subgroup of HCC specimens. Immunohistochemical analysis confirmed SALL4 expression in 55.6% of HCC specimens analyzed but not in matched non-neoplastic liver specimens. Patients with high SALL4 expression levels in their HCC tissues had a poorer prognosis than patients with low SALL4 expression levels, independent of baseline liver function. A global gene expression analysis revealed that high SALL4-expressing HCCs clustered tightly with fetal liver, and that low SALL4-expressing HCCs clustered with normal hepatocytes. Based on these results, Yong et al concluded that HCC subtypes expressing SALL4 have a progenitor-like gene signature, resulting in poor differentiation, aggressiveness, and poor prognosis. A genetic loss-of-function experiment using short hairpin RNA to examine the role of SALL4 in hepatocarcinogenesis indicated that SALL4 knockdown decreased cell viability, increased apoptosis, and decreased the tumorigenicity of HCC cells in vitro. A previous report indicated that SALL4 associates with an epigenetic modulator (nucleosome remodeling and histone deacetylase; NuRD) as a transcriptional factor to its downstream target genes. Among the target genes, the tumor suppressor phosphatase and tensin homologue (PTEN) is repressed by SALL4. The SALL4 loss-offunction microarray analysis by Yong et al revealed that the PTEN–AKT pathway is involved in SALL4-induced hepatocarcinogenesis. In a previous study, the authors demonstrated that a SALL4, 12 amino-acid peptide competitively inhibits the interaction between SALL4 and NuRD, thus blocking the NuRD-mediated SALL4-repression function. In the present study, in vitro functional assays revealed that treatment with the SALL4 peptide reduced the number of viable cells with increased levels of PTEN in a SALL4positive HCC cell line but had no effect in a cell line with undetectable endogenous SALL4 expression. The authors thus concluded that the SALL4 peptide specifically inhibits SALL4-overexpressing HCC cells but has minimal toxicity on SALL4-negative normal cells. In a mouse xenograft model, the tumor loads at 18 days were significantly smaller in mice that received the SALL4 peptide than in those that did not. Yong et al thus concluded that SALL4 plays an important role in the extensive network of heterogeneous cellular pathways underlying hepatocarcinogenesis, and that the SALL4 peptide has therapeutic potential.