Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Prospective gene expression analysis of human RNA samples from Hepatocellular Carcinoma in relation with growth rate and survival

ABSTRACT: The aim of this study is to identify by whole genome microarray expression profiling a molecular signature of HCC samples that correlates with growth rate of the tumor and survival. This signature could eventually be used as prognostic marker. The samples were prospectively derived from hepatocellular carcinoma tissue as well as non-tumor tissue from the livers of the same patients. Expression of five genes (ANGPT2, NETO2,NR4A1,DLL4,ESM1) from this signature was re-evaluated in a validation cohort by real-time PCR, confirming its correlation with growth rate and survival. The bioinformatical analysis of 161 microarray datasets were obtained from single color hybridization of human RNAs on Agilent Whole Human Genome Oligo Microarrays after T7 RNA amplification. For the purpose of this study, two discriminatory gene sets analysis were performed: up-regulated and down regulated in fast-growing tumors. For the discrimination between fast- and slow-growing tumors, the fastest quartile of the growth rate spectrum was compared with the three other quartiles. For a gene to be included, a significant discrimination (uncorrected p-value <0.01) and a 2-fold expression difference was required.

ORGANISM(S): Homo sapiens

SUBMITTER: Erica Villa

PROVIDER: E-GEOD-54236 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Disseminated tumor cells (DTCs) in the bone marrow can be detected in patients with solid tumors early on in disease progression. Via interaction with mesenchymal stromal cells (MSCs) these tumor cells may interfere with hematopoiesis. Using appropriate co-culture models, we investigated whether DTCs can change the bone marrow microenvironment by modulating MSC function with a special emphasis on their chemoattractive activity towards hematopoietic stem and progenitor cells (HSPCs). Human bone marrow derived MSCs as well as an immortalised MSC line (SCP-1) were co-cultured with MCF-7, MDA-MB231 breast carcinoma or MCF-10A non-malignant breast epithelial cells or their conditioned medium. Gene expression analysis of SCP-1 cells cultured with MCF-7 conditioned medium revealed SDF-1/CXCL12 as one of the significantly downregulated genes. Both tumor cell lines caused an inhibited SDF-1 promoter activity in SCP-1 cells, whereby MCF-7 medium decreased it to 77% and MDA-MB231 to 47%. Moreover, the SDF-1 mRNA and protein levels were significantly reduced. As a functional consequence of lower SDF-1 levels, we detected a decreased trans-well migration potential of CD34+ HSPC to MSC/tumor cell co-cultures or conditioned medium. The specificity of this chemokine mediated effect was confirmed by blocking studies with the CXCR4 antagonist AMD3100. Downregulation of SP1 transcription factor and increased miR23a levels in MSCs after contact with tumor cell medium as well as an enhanced TGFb1 expression were identified as potential molecular regulators of SDF-1 activity in MSCs. We propose an additional mechanism by which tumor cells affect the niche environment of HSPCs and therefore negatively impact hematopoiesis. Gene expression of human immortalized mesenchymal stromal cells (SCP-1) was investigated after incubation with conditioned medium of the breast carcinoma cell line MCF-7 for 24, 48, and 72 hours. Three independent experiments were performed at each time.

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Prospective gene expression analysis of human RNA samples from Hepatocellular Carcinoma in relation with growth rate and survival

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