A marker of aggressive liver cancer and potential therapeutic target identified

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1. Patients whose liver cancers had higher levels of SALL4 had a poorer prognosis.

2. SALL4 could be a therapeutic target.

Study Rundown: SALL4 encodes a transcription factor that is a known leukemia oncogene. In mouse models, SALL4 expression correlates with an embryonic progenitor cell-like pattern of gene expression. The gene is highly expressed in the fetal mouse liver, but expression gradually decreases and disappears by adulthood. In light of this, the authors hypothesized that inappropriate expression of SALL4 in adult hepatocytes might play a role in progenitor-like hepatocellular carcinomas, an aggressive subset of liver cancers.

The authors show that tissue samples of hepatocellular carcinomas with higher SALL4 expression were correlated with poorer survival. The high-SALL4 samples were enriched for genes in pathways known to be associated with worse prognosis. As this was a retrospective study, the prognostic value of SALL4 should be further evaluated in prospective trials.

The authors are enthusiastic about SALL4 as a therapeutic target because it is not expressed in normal adult tissues. The therapeutic window of a SALL4 inhibitor should therefore be quite large. In the study, the authors show that a small peptide inhibitor of SALL4 inhibits the tumorigenicity of a high-SALL4 tumor cell line both in vitro and in mouse models.

Click to read the study in the New England Journal of Medicine

Relevant Reading: Targeting transcription factor SALL4 in acute myeloid leukemia by interrupting its interaction with an epigenetic complex

In-Depth [retrospective study]: Tissue specimens of hepatocellular carcinomas from patients in Singapore and Hong Kong were analyzed for gene expression patterns via microarray. Full clinicopathological data was available for 79 samples in the Singapore specimens, allowing comparison of survival between patients with high and low-SALL4 tumors. Samples with SALL4 levels that were equal to or exceeded median SALL4 expression were classified as high-SALL4. High-SALL4 was correlated with poorer survival.

In order to explore SALL4 as a therapeutic target, the authors transplanted a high-SALL4 tumor cell line into mice and introduced a small peptide inhibitor of SALL4. The tumor load after 18 days was less in mice that received the peptide compared to mice that received a control (0.5g vs. 1.5g, p <0.05). The authors also show that the peptide does not inhibit the growth of a low-SALL4 tumor cell line, illustrating the selective toxicity of SALL4 inhibition.

By Tomi Jun and Mitalee Patil

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