Dataset Information

Oncofetal gene SALL4 in aggressive hepatocellular carcinoma.

ABSTRACT: 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.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.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.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.).

SUBMITTER: Yong KJ

PROVIDER: S-EPMC3781214 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Oncofetal gene SALL4 in aggressive hepatocellular carcinoma.

Yong Kol Jia KJ Gao Chong C Lim Joline S J JS Yan Benedict B Yang Henry H Dimitrov Todor T Kawasaki Akira A Ong Chee Wee CW Wong Kwong-Fai KF Lee Sanghoon S Ravikumar Sharada S Srivastava Supriya S Tian Xi X Poon Ronnie T RT Fan Sheung Tat ST Luk John M JM Dan Yock Young YY Salto-Tellez Manuel M Chai Li L Tenen Daniel G DG

The New England journal of medicine 20130601 24

<h4>Background</h4>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.<h4>Methods</h4>We screene ...[more]

PMID: 23758232

Similar Datasets

Project description:Sal-like protein 4 (SALL4), an embryonic stem cell transcriptional regulator, is re-expressed by an unknown mechanism in poor prognosis hepatocellular carcinoma (HCC), often associated with chronic hepatitis B virus (HBV) infection. Herein, we investigated the mechanism of SALL4 re-expression in HBV-related HCCs. We performed bisulfite sequencing PCR of genomic DNA isolated from HBV-related HCCs and HBV replicating cells, and examined DNA methylation of a CpG island located downstream from SALL4 transcriptional start site (TSS). HBV-related HCCs expressing increased SALL4 exhibited demethylation of specific CpG sites downstream of SALL4 TSS. Similarly, SALL4 re-expression and demethylation of these CpGs was observed in HBV replicating cells. SALL4 is also re-expressed in poor prognosis HCCs of other etiologies. Indeed, increased SALL4 expression in hepatitis C virus-related HCCs correlated with demethylation of these CpG sites. To understand how CpG demethylation downstream of SALL4 TSS regulates SALL4 transcription, we quantified by chromatin immunoprecipitation (ChIP) assays RNA polymerase II occupancy of SALL4 gene, as a function of HBV replication. In absence of HBV replication, RNA polymerase II associated with SALL4 exon1. By contrast, in HBV replicating cells RNA polymerase II occupancy of all SALL4 exons increased, suggesting CpG demethylation downstream from SALL4 TSS influences SALL4 transcriptional elongation. Intriguingly, demethylated CpGs downstream from SALL4 TSS are within binding sites of octamer-binding transcription factor 4 (OCT4) and signal transducer and activator of transcription3 (STAT3). ChIP assays confirmed occupancy of these sites by OCT4 and STAT3 in HBV replicating cells, and sequential ChIP assays demonstrated co-occupancy with chromatin remodeling BRG1/Brahma-associated factors. BRG1 knockdown reduced SALL4 expression, whereas BRG1 overexpression increased SALL4 transcription in HBV replicating cells. We conclude demethylation of CpGs located within OCT4 and STAT3 cis-acting elements, downstream of SALL4 TSS, enables OCT4 and STAT3 binding, recruitment of BRG1, and enhanced RNA polymerase II elongation and SALL4 transcription.

Project description:By using an expressed sequence tag bioinformatic algorithm, we identified that Lin28 homolog B (Lin28B) may have an oncofetal expression pattern which may facilitate detecting cancer cells in adults. It is also reported to be a potential marker for cancer stem cells. Therefore, we sought to verify oncofetal-stemness characters of Lin28B and test its potential as a circulating cancer stem cell-like marker in adult HCC patients. Lin28B mRNA was examined in a panel of fetal tissue, adult tissue and tumors. Lin28B was over-expressed or knocked down in HepG2 cells to evaluate its potential as a stem cell-like marker. RT-qPCR for Lin28B was performed in the peripheral blood mononuclear cells from patients with HCC receiving surgery (n=96) and non-HCC controls (n=60) and analyzed its clinical significance. Lin28B showed an oncofetal expression pattern. Its overexpression could upregulate stemness markers (OCT4, Nanog and SOX2) and enhance tumorsphere formation in vitro. Lin28B knockdown had opposite effects. Circulating Lin28B was detected in peripheral blood mononuclear cells in 3 cases (5%) of non-HCC controls and 32 cases (33.3%) of HCC patients. In HCC patients, circulating Lin28B was associated with high tumor grade (P=0.046), large size (P=0.005), high AJCC stage (P=0.044) and BCLC stage (P=0.017). Circulating Lin28B was significantly associated with decreased recurrence-free survival (P<0.001). Circulating Lin28B separated early stage HCC into 2 recurrence-free survival curves (P=0.003). In multivariate analysis, circulating Lin28B was an independent variable associated with early recurrence (P=0.045) and recurrence in early stage HCC (P=0.006). In conclusion, the oncofetal gene Lin28B is a potential oncofetal cancer-stem-cell-like circulating tumor cell marker that correlates with HCC recurrence after hepatectomy. Circulating Lin28B could refine early AJCC stages. Our finding supports the possible use of a TNMC (C for circulating tumor cells) staging system in HCC.

Dataset Information

Oncofetal gene SALL4 in aggressive hepatocellular carcinoma.

Publications

Oncofetal gene SALL4 in aggressive hepatocellular carcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets