Unknown,Transcriptomics,Genomics,Proteomics

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A novel role of stem cell factor SALL4 as an oncofetal protein in hepatocellular carcinoma

ABSTRACT: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Treatment of HCC remains abysmal; discovery of novel pathways implicated in hepatocarcinogenesis is needed for more effective therapeutics. SALL4 is a stem cell factor essential for the maintenance of embryonic stem cell self-renewal properties and expressed in fetal liver, but silenced in normal adult liver. We observed that expression of SALL4 in murine liver in a transgenic model led to development of HCC. In humans, SALL4 is re-expressed as an oncofetal protein in a subgroup of HCC patients with unfavorable prognoses. Loss-of-function studies demonstrated that SALL4 is essential for human HCC cell survival and tumorigenicity. We demonstrated that a peptide can block the oncogenic function of SALL4 in HCC by modulating the PTEN/AKT pathway. Our findings reveal a novel role of SALL4 in HCC with important implications for understanding disease mechanisms and development of innovative therapeutics. Cultured cells from HCC cell line SNU-398 with scrambled or SALL4 shRNA knockdown were used for RNA extraction and hybridization on Affymetrix microarrays.

ORGANISM(S): Homo sapiens

SUBMITTER: Henry Yang

PROVIDER: E-GEOD-35965 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Increasing studies suggest that SALL4 may play vital roles in leukemogenesis. We have used chromatin immunoprecipitation followed by microarray hybridization as a screening tool to determine potential genes that may account for the role SALL4 plays in leukemogenesis. Analysis of SALL4 binding sites reveals that genes involved in cell death, cancer, DNA replication/repair, and cell cycle were highly enriched (p<0.05). These genes include 38 important apoptosis-inducing genes (TNF, TP53, PTEN, CARD9, CARD11, CYCS, LTA) and apoptosis-inhibiting genes (Bmi-1, BCL2, XIAP, DAD1, TEGT). Real-time PCR has shown that expression levels of these genes changed significantly after SALL4 knockdown, which ubiquitously led to cell apoptosis. Flow cytometry revealed that reduction of SALL4 expression in NB4 and other leukemia cell lines dramatically increased caspase-3, Annexin V, and DNA fragmentation activity. Bromodeoxyuridine-incorporation assays showed decreased numbers of S phase cells and increased numbers of G1- and G2- phase cells indicating reduced DNA synthesis, consistent with results from cell proliferation assays. In addition, NB4 cells that express low levels of SALL4 have significantly decreased tumorigenecity in immunodeficient mice. Our studies provide a foundation in the development of leukemia stem cell-specific therapy by targeting SALL4. Keywords: ChIP-chip The global targets of SALL4 were determined using a NimbleGen promoter tiling array (2.7kb, information below) in the human cell line NB4. Because SALL4 is thought to play a significant role in leukemogenesis we focused primarily on genes involved in apoptosis and only used the ChIP-chip array as a screening tool to identify potential genes that may bind these genes. Upon identification and verification of apoptosis genes bound by SALL4 we utilized functional assays to determine the effect of SALL4 on these genes. In addition, gene expression profiling was used to determine pathways functionally altered by Sall4 reduction. Source: UCSC Build: HG18 Probe Length: 50-75mer Median Probe Spacing: 100bp Probes per Array: 385,000 Feature Size: 16Î¼m x 16Î¼m Array Dimensions: 17.4mm x 13mm Overall Slide Dimensions: 1" x 3" (25 x 75mm) Recommended Storage: Store arrays desiccated at room temperature. Promoter tiling from 2200bp upstream and 500bp downstream of the transcription start site for RefSeq genes.

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A novel role of stem cell factor SALL4 as an oncofetal protein in hepatocellular carcinoma

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