In cervical cancer, an important mechanism by which tumour cells escape immune surveillance is loss of HLA class I, enabling tumours to evade recognition and lysis by cytotoxic T lymphocytes. Some tumours, however, escape from immune surveillance without accumulating defects in antigen presentation. We hypothesized that tumours with no or partial loss of HLA class I develop alternative mechanisms to prevent immune surveillance. To investigate this hypothesis, genome-wide expression profiling using Illumina arrays was performed on cervical squamous cell carcinomas showing overall loss of HLA class I, partial and normal HLA class I protein expression. Statistical analyses revealed no significant differences in gene expression between tumours with partial (n = 11) and normal HLA class I expression (n = 10). Comparison of tumours with normal/partial HLA class I expression (n = 21) with those with overall loss of HLA class I expression (n = 11) identified 150 differentially expressed genes. Most of these genes were involved in the defense response (n = 27), and, in particular, inflammatory and acute phase responses. Especially SerpinA1 and SerpinA3 were found to be upregulated in HLA positive tumours (3.6 and 8.2 fold, respectively), and this was confirmed by real-time PCR and immunohistochemistry. In a group of 117 tumours, high SerpinA1 and SerpinA3 expression in association with normal/partial HLA expression correlated significantly with poor overall survival (p = 0.035 and p = 0.05, respectively). This study shows that HLA positive tumours are characterized by a higher expression of genes associated with an inflammatory profile and that expression of the acute phase proteins SerpinA1 and SerpinA3 in HLA positive tumours is associated with worse prognosis.
Elevated expression of SerpinA1 and SerpinA3 in HLA-positive cervical carcinoma.
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View SamplesIncreased antigen cross-presentation but impaired cross-priming after activation of PPAR is mediated by up-regulation of B7H1
Increased antigen cross-presentation but impaired cross-priming after activation of peroxisome proliferator-activated receptor gamma is mediated by up-regulation of B7H1.
Specimen part
View SamplesMicroarray-based gene expression analysis of peripheral whole blood is a common strategy in the development of clinically relevant biomarker panels for a variety of human diseases. However, the results of such an analysis are often plagued by decreased sensitivity and reliability due to the effects of relatively high levels of globin mRNA in whole blood. Globin reduction assays have been shown to overcome such effects, but they require large amounts of total RNA and may induce distinct gene expression profiles. The Illumina whole-genome DASL (WG-DASL) assay can detect gene expression levels using partially degraded RNA samples and has the potential to detect rare transcripts present in highly heterogeneous whole blood samples without the need for globin reduction. We therefore assessed the utility of the WG-DASL assay in the analysis of peripheral whole blood gene expression profiles. We find that gene expression detection is significantly increased with the use of WG-DASL compared to the standard in vitro transcription-based direct hybridization (IVT), while globin-probe-negative WG-DASL did not exhibit significant improvements over globin-probe-positive WG-DASL. Globin reduction increases the detection sensitivity and reliability of both WG-DASL and IVT with little effect on raw intensity correlations: raw intensity correlations between total RNA and globin-reduced RNA were 0.970 for IVT and 0.981 for WG-DASL. Overall, the detection sensitivity of the WG-DASL assay is higher than the IVT-based direct hybridization assay, with or without globin reduction, and should be considered in conjunction with globin reduction methods for future blood-based gene expression studies.
Gene expression profiling of human whole blood samples with the Illumina WG-DASL assay.
Specimen part
View SamplesResistance to platinum-based chemotherapy is a clinical challenge in the treatment of ovarian cancer (OC) and limits survival. Therefore, innovative drugs against platinum-resistance are urgently needed. Our therapeutic concept is based on the conjugation of two chemotherapeutic compounds to a monotherapeutic pro-drug, which is taken up by cancer cells and cleaved into active cytostatic metabolites. Here, we explore the activity of the duplex-prodrug 5-FdU-ECyd, covalently linking 2''-deoxy-5-fluorouridine (5-FdU) and 3''-C-ethynylcytidine (ECyd), on platinum-resistant OC cells. RNA-Sequencing was used for characterization of 5-FdU-ECyd treated platinum-sensitive A2780 and isogenic platinum-resistant A2780cis. Overall design: Platinum-sensitive A2780 and platinum resistant-cells A2780cis were treated with 5-FdU-Ecyd for 6h and 12h, there are also 6h and 12h untreated controls, all groups are in triplicates
The conjugated antimetabolite 5-FdU-ECyd and its cellular and molecular effects on platinum-sensitive vs. -resistant ovarian cancer cells <i>in vitro</i>.
Cell line, Subject, Time
View SamplesNeuromedin U (NMU), which is thought to contribute to putative metastasis processes in various tumor entities, was identified as being up-regulated in breast cancer. Therefore, we aimed to uncover the role of NMU in breast cancer subtypes deciphering for the first time NMU-driven signalling pathways and downstream targets.
Oncogenic features of neuromedin U in breast cancer are associated with NMUR2 expression involving crosstalk with members of the WNT signaling pathway.
Sex, Age, Specimen part, Cell line, Race
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Genetic and genomic analyses of RNA polymerase II-pausing factor in regulation of mammalian transcription and cell growth.
Specimen part, Treatment
View SamplesMany mammalian genes are occupied by paused RNA polymerase II (pol II) at promoter-proximal regions on both sides of transcription start sites (TSSs). However, the consequences of pol II pausing on gene expression and cell biology are not fully understood. Here we report that genetic ablation of the b subunit of mouse negative elongation factor (Nelf-b), a key pol II-pausing factor, results in slower progression at multiple cell cycle stages and increased apoptosis. Consistently, a whole-genome analysis indicates that growth and cell death-related genes are highly enriched among the direct target genes of Nelf-b. In particular, Nelf-b deletion increases pol II density in the promoter-distal region of stress response genes and their overall expression levels in the absence of any external stress signals. In addition, our work also reveals a previously unappreciated role of Nelf-b role in curbing TSS-upstream transcription of many mammalian genes. We suggest that Nelf-mediated pol II pausing balances the cellular needs for growth/survival and stress response by preventing excessive basal transcription of stress-induced genes.
Genetic and genomic analyses of RNA polymerase II-pausing factor in regulation of mammalian transcription and cell growth.
Specimen part, Treatment
View SamplesPHD4 regulates the expression of Hypxia-inducible Factor 2 (HIF-2) alpha in LM8 osteosarcoma cells. PHD4 overexpression inhibits the growth of experimental tumor in syngenic mice but stimulates angiogenesis via Transforming Growth-Factor (TGF)-alpha.
PHD4 stimulates tumor angiogenesis in osteosarcoma cells via TGF-α.
Cell line, Treatment
View SamplesNeuroprotective effects of NDP-MSH. We have characterized the signaling down-stream of melanocortin-1 receptor ligation to identify pathways mediating neuroprotective effects of NDP-MSH using transcriptional profiling. In this data set we included the expression data obtained from mouse brain tissue (MOG-immunized wild-type or C57BL/6Je/e mice at disease maximum, d14 after immunization). The data were used to obtain differentially regulated genes in wild-type or C57BL/6Je/e mice upon systemic NDP-MSH treatment.
Melanocortin-1 receptor activation is neuroprotective in mouse models of neuroinflammatory disease.
Specimen part, Treatment
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Multi-platform assessment of transcriptional profiling technologies utilizing a precise probe mapping methodology.
Specimen part, Disease
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