FOXO transcription factors control cellular formation of reactive oxygen species (ROS), which critically contribute to cell survival and cell death in neuroblastoma. Here, we report that C10orf10, also named Decidual Protein induced by Progesterone (DEPP), is a direct transcriptional target of FOXO3 in human neuroblastoma. As FOXO3-mediated apoptosis involves a biphasic ROS accumulation, we analyzed cellular ROS levels in DEPP-knockdown cells by live-cell imaging. Knockdown of DEPP prevented the primary and secondary ROS accumulation during FOXO3 activation and attenuates FOXO3-induced apoptosis, whereas its overexpression raises cellular ROS levels and sensitizes to cell death. In neuronal cells, cellular steady state ROS are mainly detoxified in peroxisomes by the enzyme CAT/catalase. As DEPP contains a peroxisomal-targeting-signal-type-2 (PTS2) sequence at its N-terminus that enables protein import into peroxisomes, we analyzed the effect of DEPP on peroxisomal function by measuring the catalase enzyme activity. Catalase activity was reduced by conditional DEPP overexpression and significantly increased in DEPP-knockdown cells. Using live cell imaging and fluorescent peroxisomal and mitochondrial probes we demonstrate that DEPP localizes to peroxisomes and mitochondria in neuroblastoma cells. The combined data indicate that DEPP reduces peroxisomal activity and thereby impairs the cellular ROS detoxification capacity and contributes to death sensitization.
C10ORF10/DEPP, a transcriptional target of FOXO3, regulates ROS-sensitivity in human neuroblastoma.
Cell line, Treatment
View SamplesGene expression profile of cancer cell lines of breast, lung, pancreatic, gasctric, ovarian, hepatocellular, prostate carcinomas and melanomas.
Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations.
No sample metadata fields
View SamplesExon usage analysis in in vitro cultured fibroblast cells. To assay the genome-wide splicing changes during cellular senescence, we performed splicing analysis on young and old normal fibroblasts, and in fibroblasts +/- tert (telomerase protein subunit Tert immortalized).
Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts.
Specimen part, Disease, Disease stage, Subject
View SamplesIn order to understand differentially regulated gene expression after the different treatments, 4 size matched tumors of each group were analyzed by microarrays.
Regulation of myeloid cells by activated T cells determines the efficacy of PD-1 blockade.
Specimen part
View SamplesWe sought to determine what if any changes dendritic cells induce in melanocytes when they are grown together (co-cultured)
Dendritic cells are contained within melanocytic nevus nests in vivo and can alter gene expression of epidermal melanocytes in vitro.
No sample metadata fields
View SamplesNOTCH1 is mutationally activated in ~15% of cases of chronic lymphocytic leukaemia (CLL), but its role in B-cell development and leukemogenesis is not known. Here, we report that the active intracellular portion of NOTCH1 (ICN1) is detectable in ~50% of peripheral blood CLL cases lacking gene mutations. We identify a ‘NOTCH1 CLL gene expression signature’ in CLL cells, and show that this signature is significantly enriched in primary CLL cases expressing ICN1, independent of NOTCH1 mutation. NOTCH1 target genes include key regulators of B-cell proliferation, survival and signal transduction physiology. In particular, we show that MYC is a direct target of NOTCH1 via B-cell specific distal regulatory elements, thus implicating this oncogene in the pathogenesis of the disease. Overall design: RNA-Seq analysis
Common nonmutational <i>NOTCH1</i> activation in chronic lymphocytic leukemia.
Specimen part, Subject
View SamplesTreatment of hematological malignancies by adoptive transfer of activated natural killer (NK) cells is limited by poor post-infusion persistence. We compared the ability of interleukin-2 (IL-2) and IL-15 to sustain human NK cell functions following cytokine withdrawal to model post-infusion performance. In contrasts to IL-2, IL-15 mediated stronger signaling through the IL-2/15 receptor complex and provided functional advantages. Genome-wide analysis of cytosolic and polysome-associated mRNA revealed cytokine dependent differential mRNA levels and translation during cytokine activation but also that most gene expression differences were primed by IL-15 and only manifested after cytokine withdrawal. IL-15 augmented mTOR signaling, which correlated with increased expression of genes related to cell metabolism and respiration. Consistently, mTOR inhibition abrogated IL-15-induced functional advantages. Moreover, mTOR-independent STAT-5 signaling contributed to improved NK cell function during cytokine activation but not following cytokine withdrawal. The superior performance of IL-15 stimulated NK cells was also observed using a clinically applicable protocol for NK cell expansion. Finally, expression of IL-15 correlated with cytolytic immune functions in patients with B cell lymphoma and favorable clinical outcome. These findings highlight the importance of mTOR regulated metabolic processes for immune cell functions and argue for implementation of IL-15 in adoptive NK cell cancer therapy. Overall design: Freshly isolated NK cells from 6 donors were activated with IL-2 or IL-15 for 48 hours, followed by cytokine withdrawal for 24 hours, resulting in four RNA samples per donor. From each sample, both the cytosolic as well as the polysomal fraction were collected. Donor 3 contains activation and post withdrawal data from two different donors due to poor RNA-quality obtained for some samples which did not allow for processing of the complete set of 6 donors (resulting in a total of 40 samples).
IL-15 activates mTOR and primes stress-activated gene expression leading to prolonged antitumor capacity of NK cells.
No sample metadata fields
View SamplesWe used Affymetrix HG U133 Plus 2.0 GeneChips to compare the transcriptome of miR-145-overexpressing MDA-MB-231 cells against negative control miRNA precursor-transfected cells.
miR-145-dependent targeting of junctional adhesion molecule A and modulation of fascin expression are associated with reduced breast cancer cell motility and invasiveness.
Specimen part
View SamplesExpression data of BL2 Burkitt Lymphoma cell line (controls and samples treated with different B cell specific stimuli)
Global gene expression changes of in vitro stimulated human transformed germinal centre B cells as surrogate for oncogenic pathway activation in individual aggressive B cell lymphomas.
Specimen part, Cell line
View SamplesCellular and molecular differences between DNs and CMNs are not completely understood. Using cDNA microarray, quantitative RT-PCR, and immunohistochemistry, we molecularly characterized DNs and analyzed the difference between DNs and CMNs.
Discrimination of Dysplastic Nevi from Common Melanocytic Nevi by Cellular and Molecular Criteria.
Specimen part
View Samples