Filters
Technology
Platform
GSE73571
Homo sapiens
16 Downloadable Samples
Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
OBJECTIVE: Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterize the role of tumor-initiating cells (T-ICs) and signaling pathways involved in sorafenib resistance. DESIGN: HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: 1) Role of T-ICs by in vitro sphere formation and in vivo tumorigenesis assays using NOD/SCID mice, 2) Activation of alternative signaling pathways and 3) Efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, qRT-PCR) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in 2 independent cohorts. RESULTS: Sorafenib-acquired resistance tumors showed significant enrichment of T-ICs (164 cells needed to create a tumor) vs. sorafenib-sensitive tumors (13400 cells) and non-treated tumors (1292 cells), p<0.001. Tumors with sorafenib-acquired resistance were enriched with IGF and FGF signaling cascades (FDR<0.05). In vitro, cells derived from sorafenib-acquired resistant tumors and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumor growth and improved survival in sorafenib-resistant tumors. A sorafenib-resistance 175-gene signature was characterized by enrichment of progenitor-cell features, aggressive tumoral traits and predicted poor survival in 2 cohorts (n=442 HCC patients). CONCLUSION: Acquired resistance to sorafenib is driven by tumor initiating cells with enrichment of progenitor markers and activation of IGF and FGF signaling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression.
Publication Title
Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma.
Sample Metadata Fields
No sample metadata fields
View Samples- Caenorhabditis elegans
- 43 Downloadable Samples
Illumina HiSeq 1500, Illumina Genome Analyzer IIx
Description
C. elegans totalRNA profiles of worms treated with RNAi for different Integrator complex genes or L4440 (Control). Worms were grown at 15ºC and samples were taken six days after silencing Overall design: C. elegans totalRNA profiles of worms treated with RNAi for different Integrator complex genes or L4440 (Control). Three replicates per sample. Deep sequencing in Illumina HiSeq1500.
Publication Title
Disruption of the Caenorhabditis elegans Integrator complex triggers a non-conventional transcriptional mechanism beyond snRNA genes.
Sample Metadata Fields
Subject
View Samples- Homo sapiens
- 91 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Gene-expression signature of vascular invasion in hepatocellular carcinoma.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Homo sapiens
- 97 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor due to activation of multiple cellular pathways and molecular alterations. Herein, we report the first molecular classification of 89 HCC based on the expression of 358 microRNAs and integrative genomic analysis. Three main subclasses of HCC were identified : two of them were associated with beta-catenin mutations or aggressive phenotype. A subset of the subclass of aggressive tumors (8/89, 9%) showed overexpression of a cluster of microRNAs located on chr19q13.41 (C19MC locus. We showed that miR 517a, representing C19MC, promoted cell proliferation, migration and invasion in vitro and induced the development of aggressive tumors in vivo suggesting its role as a novel oncogenic driver in HCC.
Publication Title
MicroRNA-based classification of hepatocellular carcinoma and oncogenic role of miR-517a.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Homo sapiens
- 6 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
mRNA expression profile modified by stable transfection of microRNA mir-517a (MIR517A) in a human hepatocellular carcinoma cell line Huh-7
Publication Title
MicroRNA-based classification of hepatocellular carcinoma and oncogenic role of miR-517a.
Sample Metadata Fields
No sample metadata fields
View Samples- Caenorhabditis elegans
- 18 Downloadable Samples
- Illumina HiSeq 2500
Description
The transcriptomes of model organisms have been defined under specific laboratory growth conditions. The standard protocol for Caenorhabditis elegans growth and maintenance is 20ºC on an Escherichia coli diet. Temperatures ranging from 15ºC to 25ºC or feeding with other species of bacteria are considered physiological lab conditions, but the effect of these conditions on the worm transcriptome have not been well characterized. Here, we compare the global patterns of gene expression for the reference Caenorhabditis elegans strain (N2) grown at 15oC, 20oC, and 25oC on two different diets, Escherichia coli and Bacillus subtilis. When C. elegans were fed E. coli and the growth temperature was increased, we observed an enhancement of defense response pathways and down-regulation of genes associated with metabolic functions. However, when C. elegans were fed B. subtilis and the growth temperature was increased, the nematodes exhibited a decrease in defense response pathways and an enhancement of expression of genes associated with metabolic functions. Our results show that C. elegans undergo significant metabolic and defense response changes when the maintenance temperature fluctuates within the physiologically accepted experimental range and that the degree of pathogenicity of the bacterial diet can further alter the worm transcriptome. Overall design: C. elegans mRNA profiles at different temperatures and feeding in six samples, three replicates per sample. Deep sequencing in Illumina HiSeq2500.
Publication Title
Effect of the diet type and temperature on the <i>C. elegans</i> transcriptome.
Sample Metadata Fields
Subject
View Samples- Homo sapiens
- 37 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
The aim of this study was to identify the genes showing an altered expression in LGMD2A patients and the possible pathways they are implicated in. Ten muscle samples from patients with calpainopathy in which molecular diagnosis was ascertained were invest
Publication Title
Gene expression profiling in limb-girdle muscular dystrophy 2A.
Sample Metadata Fields
Sex
View Samples- Homo sapiens
- 18 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
The pesticide rotenone, a neurotoxin that inhibits the mitochondrial complex I, and destabilizes microtubules (MT) has been linked to Parkinson disease (PD) etiology and is often used to model this neurodegenerative disease (ND). Many of the mechanisms of action of rotenone are posited mechanisms of neurodegeneration; however, they are not fully understood. Therefore, the study of rotenone-affected functional pathways is pertinent to the understanding of NDs pathogenesis. This report describes the transcriptome analysis of a neuroblastoma (NB) cell line chronically exposed to marginally toxic and moderately toxic doses of rotenone. The results revealed a complex pleiotropic response to rotenone that impacts a variety of cellular events, including cell cycle, DNA damage response, proliferation, differentiation, senescence and cell death, which could lead to survival or neurodegeneration depending on the dose and time of exposure and cell phenotype. The response encompasses an array of physiological pathways, modulated by transcriptional and epigenetic regulatory networks, likely activated by homeostatic alterations. Pathways that incorporate the contribution of MT destabilization to rotenone toxicity are suggested to explain complex I-independent rotenone-induced alterations of metabolism and redox homeostasis. The postulated mechanisms involve the blockage of mitochondrial voltage-dependent anions channels (VDACs) by tubulin, which coupled with other rotenone-induced organelle dysfunctions may underlie many presumed neurodegeneration mechanisms associated with pathophysiological aspects of various NDs including PD, AD and their variant forms. Thus, further investigation of such pathways may help identify novel therapeutic paths for these NDs.
Publication Title
Transcriptome analysis of a rotenone model of parkinsonism reveals complex I-tied and -untied toxicity mechanisms common to neurodegenerative diseases.
Sample Metadata Fields
Cell line, Treatment, Time
View Samples- Mus musculus
- 1 Downloadable Sample
- Affymetrix Mouse Expression 430A Array (moe430a)
Description
Alpha synuclein (SNCA) has been linked to neurodegenerative diseases (synucleinopathies) that include Parkinsons disease (PD). Although the primary neurodegeneration in PD involves nigrostriatal dopaminergic neurons, more extensive yet regionally selective neurodegeneration is observed in other synucleinopathies. Furthermore, SNCA is ubiquitously expressed in neurons and numerous neuronal systems are dysfunctional in PD. Therefore it is of interest to understand how overexpression of SNCA affects neuronal function in regions not directly targeted for neurodegeneration in PD. To gain a better understanding of the consequences of excessive SNCA expression on basal ganglia function, we performed transcriptome analysis of striatal tissue from male Thy1-aSyn-mice and wt littermates. The present study investigated the consequences of SNCA overexpression on cellular processes and functions in the striatum of mice overexpressing wild-type, human SNCA under the Thy1 promoter (Thy1-aSyn mice) by transcriptome analysis. The analysis revealed alterations in multiple biological processes in the striatum of Thy1-aSyn mice, including synaptic plasticity, signaling, transcription, apoptosis, and neurogenesis.
Publication Title
Analysis of striatal transcriptome in mice overexpressing human wild-type alpha-synuclein supports synaptic dysfunction and suggests mechanisms of neuroprotection for striatal neurons.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Homo sapiens
- 22 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Tolerogenic dendritic cells (tol-DCs) offer a promising therapeutic potential for autoimmune diseases. Tol-DCs have been reported to inhibit immunogenic responses, yet little is known about the mechanisms controlling their tolerogenic status, as well as associated specific markers. Here we show that the anti-inflammatory TAM receptor tyrosine kinase MERTK, is highly expressed on clinical grade dexamethasone-induced human tol-DCs and mediates their tolerogenic effect. Neutralization of MERTK in allogenic mixed lymphocyte reactions as well as autologous DC-T cell cultures leads to increased T cell proliferation and IFN-g production. Additionally, we identify a previously unrecognized non-cell autonomous regulatory function of MERTK expressed on DCs. Recombinant Mer-Fc protein, used to mimic MERTK on DCs, suppresses nave and antigen-specific memory T cell activation. This mechanism is mediated by the neutralization of the MERTK agonist Protein S (PROS1) expressed by T cells. We find that MERTK and PROS1 are expressed in human T cells upon TCR activation and drive an autocrine pro-proliferative mechanism. Collectively, these results suggest that MERTK on tol-DCs directly inhibits T cell activation through the competition for PROS1 interaction with MERTK in the T cells. Targeting MERTK may provide an interesting approach to effectively increase or suppress tolerance for the purpose of immunotherapy.
Publication Title
MERTK as negative regulator of human T cell activation.
Sample Metadata Fields
No sample metadata fields
View Samples