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GSE49232
Homo sapiens
4 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
A large body of evidence has demonstrated that many human tumors are maintained by a small cell population called cancer stem cells (CSCs) or tumor progenitors, which are responsible for tumor formation, therapy resistance and metastasis. We found that ionizing radiation treatment enriches for the CSC phenotype and properties by preferential survival and expansion of tumor progenitor cells. Our studies revealed that aldehyde dehydrogenase (ALDH) activity is indicative of prostate tumor progenitor cells with increased chemo- and radioresistance, enhanced migratory potential, improved DNA- double strand break repair and activation of the signaling pathways, which promote self-renewal and epithelial-mesenchymal transition. We found that X-ray irradiation can convert the bulk tumor cells to more clonogenic and radioresistant population positive for expression of CSC markers. For the first time we showed that irradiation increases histone H3K4 and H3K36 methylation in prostate cancer cells, thereby reactivating transcription of epigenetically silenced target genes. We showed that radioresistant tumor progenitor population undergoes a phenotypical switching during the course of irradiation, suggesting that controlling the phenotypical and functional properties of CSCs during radiation therapy is ultimative for the optimization of treatment strategies. Our studies have shown that CSC markers may be beneficial in prediction of tumor radiocurability, and combination of irradiation with therapies directed against CSCs can be a useful strategy to improve cancer treatment.
Publication Title
Aldehyde Dehydrogenase Is Regulated by β-Catenin/TCF and Promotes Radioresistance in Prostate Cancer Progenitor Cells.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 32 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
MYC translocations are the biologic hallmark of Burkitt lymphomas but also occur in other mature B-cell lymphomas. If accompanied by chromosomal breaks targeting the BCL2 and/or BCL6 oncogenes, these MYC translocation-positive (MYC+) lymphomas are called double-hit lymphomas (DHLs); otherwise, the term single-hit lymphoma (SHL) is applied. In order to characterize the biologic features of these MYC+ lymphomas other than Burkitt lymphomas, we explored, after exclusion of molecular Burkitt lymphoma (mBL) as defined by gene expression profiling (GEP), the molecular, pathological and clinical aspects of 80 MYC translocation (MYC+) lymphomas (31 SHL, 26 BCL2+/MYC+, 14 BCL6+/MYC+, 6 BCL2+/BCL6+/MYC+ and 3 MYC+ lymphomas with unknown BCL6 status). Comparison of SHL and DHL revealed no difference in frequency of MYC partner (IG/non-IG), genomic complexity or MYC expression and no differences in GEP. DHL showed a more frequent GCB-like GEP and higher IGH and MYC mutation rates. GEP revealed 130 differentially expressed genes between BCL6+/MYC+ and BCL2+/MYC+ DHL. BCL2+/MYC+ DHL showed a more frequent GCB-like GEP. Analysis of all lymphomas according to MYC partner (IG/non-IG) revealed no substantial differences. In contrast to mBL and lymphomas without MYC break, SHL and DHL patients had similar poor outcome. Our data suggest that after excluding mBL, MYC+ lymphomas could be biologically widely lumped without further need for subclassification.
Publication Title
Biological characterization of adult MYC-translocation-positive mature B-cell lymphomas other than molecular Burkitt lymphoma.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 9 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Overexpression of p21 in NEMOhepa animals protects against DNA damage, acceleration of hepatocarcinogenesis and cholestasis. As strengthened by our LPS stimulation experiments, we identified a novel protective role of p21 against DNA damage.
Publication Title
p21 ablation in liver enhances DNA damage, cholestasis, and carcinogenesis.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 219 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
The distinction between the Burkitt lymphoma and diffuse large B-cell lymphoma is imprecise using current diagnostic criteria. We applied transcriptional and genomic profiling to molecularly define Burkitt lymphoma. Gene expression profiling employing Affymetrix GeneChips (U133A) was performed in 220 mature aggressive B-cell lymphomas, including a core group of eight Burkitt lymphomas, which fulfilled all diagnostic criteria of the WHO classification. A molecular signature of Burkitt lymphoma was generated. Chromosomal abnormalities were detected by interphase fluorescence in-situ hybridization and array comparative genomic hybridization. The molecular Burkitt lymphoma signature identified 44 cases. Fifteen of these cases lacked a morphology typical for Burkitt/Burkitt-like lymphoma. The vast majority (88%) of the 176 lymphomas without the molecular Burkitt lymphoma signature represented diffuse large B-cell lymphomas. In 20% of these cases a MYC break was detectable which was associated with complex chromosomal changes. Our molecular definition of Burkitt lymphoma sharpens and extends the spectrum of Burkitt lymphoma. In mature aggressive B-cell lymphomas without a Burkitt lymphoma signature, a chromosomal break in the MYC locus proved to be associated with adverse clinical outcome.
Publication Title
A biologic definition of Burkitt's lymphoma from transcriptional and genomic profiling.
Sample Metadata Fields
Sex, Age
View Samples- Homo sapiens
- 271 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
Background: Germinal center B-cell (GCB) lymphomas are common in children and adults. The prognosis strongly depends on age. Subgroups of GCB-lymphomas are characterized by chromosomal translocations affecting immunoglobulin (IG) loci leading to oncogene deregulation.
Publication Title
Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults.
Sample Metadata Fields
Sex, Age
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Gene 1.1 ST Array (mogene11st)
Description
Hepatic fibrosis is a wound-healing response to chronic liver injury, which may result in cirrhosis and liver failure. The c-Jun N-terminal kinase-1 (JNK1) gene has been shown to be involved in liver fibrosis. Here, we aimed to investigate the molecular mechanism and identify the cell-type involved in mediating the JNK1-dependent effect on liver fibrogenesis Wild-type (WT), JNK1/ and JNK1hepa (hepatocyte-specific deletion of JNK1) mice were subjected to bile duct ligation (BDL). Additionally, we performed bone marrow transplantations (BMT), isolated primary hepatic stellate cells (HSCs) and studied their activation in vitro. Serum markers of liver damage (liver transaminases, alkaline phosphatase and bilirubin) and liver histology revealed reduced injury in JNK1/ compared to WT and JNK1hepa mice. Hepatocyte cell death and proliferation was reduced in JNK1/ compared to WT and JNK1hepa. Parameters of liver fibrosis such as Sirius Red staining as well as Collagen IA1 and SMA expression were down-regulated in JNK1/ compared to WT and JNK1hepa livers, 4 weeks after BDL. To delineate the essential cell-type, we performed BMT of WT and JNK1-/- into JNK1-/- and WT mice, respectively. BMT experiments excluded bone marrow derived cells from having a major impact on the JNK1-dependent effect on fibrogenesis. Hence, we investigated primary HSCs from JNK1/ livers showing reduced transdifferentiation compared with WT and JNK1hepa-derived HSCs. We conclude that JNK1 in HSCs plays a crucial role in hepatic fibrogenesis and thus represents a promising target for cell-directed treatment options for liver fibrosis.
Publication Title
Jnk1 in murine hepatic stellate cells is a crucial mediator of liver fibrogenesis.
Sample Metadata Fields
Sex, Age, Specimen part, Treatment, Time
View Samples- Mus musculus
- 11 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury and cancer. Deletion of NF-B essential modulator in hepatocytes (Nemohepa) causes the spontaneous development of hepatocellular carcinoma preceded by steatohepatitis in mice and thus serves as an excellent model for the progression from chronic hepatitis to liver cancer. In the present study we aimed to dissect the death-receptor mediated pathways that contribute to liver injury in Nemohepa mice. Therefore, we generated Nemohepa/TRAIL-/- and Nemohepa/TNFR1-/- animals and analyzed the progression of liver injury. Nemohepa/TRAIL-/- displayed a similar phenotype to Nemohepa mice characteristic of high apoptosis, infiltration of immune cells, hepatocyte proliferation and steatohepatitis. These pathophysiological features were significantly ameliorated in Nemohepa/TNFR1-/- livers. Hepatocyte apoptosis was increased in Nemohepa and Nemohepa/TRAIL-/- mice while Nemohepa/TNFR1-/- animals showed reduced cell death concomitant with a strong reduction in pJNK levels. Cell cycle parameters were significantly less activated in Nemohepa/TNFR1-/- livers. Additionally, markers of liver fibrosis and indicators of tumour progression were significantly decreased in these animals. The present data demonstrate that the death receptor TNFR1 but not TRAIL is important in determining progression of liver injury in hepatocyte-specific Nemo knockout mice.
Publication Title
TNFR1 determines progression of chronic liver injury in the IKKγ/Nemo genetic model.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Gene 1.1 ST Array (mogene11st)
Description
Aberrant biliary hyperproliferation resulting from lack of differentiating signals favoring the maintenance of an immature and proliferative phenotype by biliary epithelial cells are ultimately responsible for ducto/cystogenesis and intrahepatic cholangiocarcinoma (CCA) formation. Mitogen-activated protein kinase (MAPK) signaling is pivotal for CCA-related tumorigenesis. In particular, targeted inhibition of JNK signaling has shown therapeutic potential. However, the cell-type specific role and mechanisms triggered by JNK in liver parenchymal cells during CCA remains largely unknown. Here, we aimed to investigate the relevance of JNK function in hepatocytes in experimental carcinogenesis. JNK signaling in hepatocytes was inhibited by crossing AlbCre-JNK1LoxP/LoxP mice with JNK2-deficient mice to generate Jnk1LoxP/LoxP/Jnk2−/− (JNKΔhepa) mice. JNKΔhepa mice were further interbred with hepatocyte-specific Nemo-knockout mice (NEMOΔhepa), a model of chronic liver inflammation and spontaneous hepatocarcinogenesis, to generate NEMO/JNKΔhepa mice. The impact of JNK deletion on liver damage, cell death, compensatory proliferation, fibrogenesis, and tumor development in NEMOΔhepa mice was determined. Moreover, regulation of essential genes was assessed by RT-PCR, immunoblottings and immunostains. Additionally, JNK2 inhibition, specifically in hepatocytes of NEMOΔhepa/JNK1Δhepa mice, was performed using siRNA (siJnk2) nanodelivery. Finally, active signaling pathways were blocked using specific inhibitors. Compound deletion of JNK1 and JNK2 in hepatocytes diminished hepatocarcinogenesis in both the DEN model of hepatocarcinogenesis and in NEMOΔhepa mice, but, in contrast, caused massive proliferation of the biliary ducts. Indeed, JNK deficiency in hepatocytes of NEMOΔhepa (NEMOΔhepa/JNKΔhepa) animals caused elevated fibrosis, increased apoptosis, increased compensatory proliferation, and elevated inflammatory cytokines expression, but reduced hepatocarcinogenesis. Furthermore, siJnk2 treatment in NEMOΔhepa/JNK1Δhepa mice recapitulated the phenotype of NEMOΔhepa/JNKΔhepa mice. Next, we sought to investigate the impact of molecular pathways in response to compound JNK deficiency in NEMOΔhepa mice. We found that NEMOΔhepa/JNKΔhepa livers exhibited overexpression of the IL-6/Stat3 pathway in addition to EGFR-Raf-MEK-ERK cascade. The functional relevance was tested by administering lapatinib - a dual tyrosine kinase inhibitor (TKI) of ErbB2 and EGFR signaling - to NEMOΔhepa/JNKΔhepa mice. Lapatinib effectively inhibited cystogenesis, improved transaminases and effectively blocked EGFR-Raf-MEK-ERK signaling. Our study defines a novel function of JNK in cell fate as well as hepatocarcinogenesis and opens new therapeutic avenues devised to inhibit pathways of cholangiocarcinogenesis.
Publication Title
Loss of c-Jun N-terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma.
Sample Metadata Fields
Age, Specimen part, Treatment
View Samples- Homo sapiens
- 332 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Host Transcription Profile in Nasal Epithelium and Whole Blood of Hospitalized Children Under 2 Years of Age With Respiratory Syncytial Virus Infection.
Sample Metadata Fields
Sex, Age, Specimen part, Disease, Disease stage
View Samples- Mus musculus
- 17 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Tumor growth is associated with a profound alteration of myelopoiesis, leading to recruitment of immunosuppressive cells known as myeloid-derived suppressor cells (MDSCs). Immuno-regulatory activity of both tumor-induced and BM-derived MDSCs (by GM-CSF and IL-6 treatment) was entirely dependent on C/EBP transcription factor (TF), a key component of the emergency myelopoiesis triggered by stress and inflammation. We used miR expression analysis to identify miRs which could drive MDSC recruitment/generation/activity by modulating specific TFs and pathway. In particular, we identified a miR signature of 79 miR differentially expressed between not suppressive CD11b+ cells and CD11b+ isolated from tumor mass and spleen of tumor-bearing mice. Moreover on the same samples we profiled gene expression with Affymetrix microarrays to perform an integrated analysis of mirna and gene expression.
Publication Title
miR-142-3p prevents macrophage differentiation during cancer-induced myelopoiesis.
Sample Metadata Fields
Specimen part, Disease, Disease stage, Cell line
View Samples