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  • EXPRESSION  (29)
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  • 11
    Keywords: CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; INVASION ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; Germany ; CLASSIFICATION ; GENE-EXPRESSION ; GENOME ; PROTEIN ; PROTEINS ; TUMORS ; TIME ; kidney ; primary ; FLOW ; BIOLOGY ; CELL-CYCLE ; MOLECULAR-BIOLOGY ; BREAST ; breast cancer ; BREAST-CANCER ; PROGRESSION ; PATTERNS ; MEMBRANE ; METASTASIS ; genetics ; metastases ; CANCER-CELLS ; ONCOGENE ; heredity ; molecular biology ; molecular ; E-cadherin ; ONCOLOGY ; RE ; INCREASE ; LEVEL ; LOSSES ; REDUCED EXPRESSION ; ENGLAND ; INCREASES ; detachment ; cell junctions ; initial cell-cell contact
    Abstract: Vacuole membrane protein 1 (Vmp1) is described as a cancer-relevant cell cycle modulator, but the function of this protein and its mode of action in tumor progression are still unknown. In this study, we show that the VMP1 mRNA level is significantly reduced in kidney cancer metastases as compared to primary tumors. Further, VMP1 expression is also decreased in the invasive breast cancer cell lines HCC1954 and MDA-MB-231 as compared to the non-invasive cell lines MCF-12A, T-47D and MCF-7. We show for the first time that Vmp1 is a plasma membrane protein and an essential component of initial cell-cell contacts and tight junction formation. It interacts with the tight junction protein Zonula Occludens-1 and colocalizes in spots between neighboring HEK293 cells. Downregulation of VMP1 by RNAi results in loss of cell adherence, and increases the invasion capacity of the non-invasive kidney cancer cell line Caki-2. In conclusion, our findings establish Vmp1 to be a novel cell-cell adhesion protein and that its expression level determines the invasion and metastatic potential of cancer cells
    Type of Publication: Journal article published
    PubMed ID: 17724469
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  • 12
    Keywords: EXPRESSION ; transcription ; TISSUE ; TUMORS ; IDENTIFICATION ; PATTERN ; SPECTRUM ; NAB2 ; STAT6 ; HEMANGIOPERICYTOMA
    Abstract: Recurrent somatic fusions of the two genes, NGFI-A-binding protein 2 (NAB2) and STAT6, located at chromosomal region 12q13, have been recently identified to be presumable tumor-initiating events in solitary fibrous tumors. Herein, we evaluated a cohort of 52 solitary fibrous tumors/hemangiopericytomas by whole-exome sequencing (one case) and multiplex RT-PCR (all 52 cases), and identified 12 different NAB2-STAT6 fusion variants in 48 cases (92%). All 52 cases showed strong and diffuse nuclear positivity for STAT6 by IHC. We categorized the fusion variants according to their potential functional effects within the predicted fusion protein and found strong correlations with relevant clinicopathological features. Tumors with the most common fusion variant, NAB2ex4-STAT6ex2/3, corresponded to classic pleuropulmonary solitary fibrous tumors with diffuse fibrosis and mostly benign behavior and occurred in older patients (median age, 69 years). In contrast, tumors with the second most common fusion variant, NAB2ex6-STAT6ex16/17, were found in much younger patients (median age, 47 years) and represented typical hemangiopericytomas from deep soft tissue with a more aggressive phenotype and clinical behavior. In summary, these molecular genetic findings support the concept that classic pleuropulmonary solitary fibrous tumor and deep-seated hemangiopericytoma are separate entities that share common features but correlate to different clinical outcome.
    Type of Publication: Journal article published
    PubMed ID: 24513261
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  • 13
    Keywords: EXPRESSION ; CELL-PROLIFERATION ; THERAPY ; GROWTH-FACTOR RECEPTOR ; BREAST-CANCER ; ESTROGEN-RECEPTOR ; MAMMARY-GLAND ; MOUSE-LIVER ; CIRCADIAN CLOCK ; CORTISOL RHYTHM
    Abstract: Signal transduction by receptor tyrosine kinases (RTKs) and nuclear receptors for steroid hormones is essential for body homeostasis, but the cross-talk between these receptor families is poorly understood. We observed that glucocorticoids inhibit signalling downstream of EGFR, an RTK. The underlying mechanism entails suppression of EGFR's positive feedback loops and simultaneous triggering of negative feedback loops that normally restrain EGFR. Our studies in mice reveal that the regulation of EGFR's feedback loops by glucocorticoids translates to circadian control of EGFR signalling: EGFR signals are suppressed by high glucocorticoids during the active phase (night-time in rodents), while EGFR signals are enhanced during the resting phase. Consistent with this pattern, treatment of animals bearing EGFR-driven tumours with a specific kinase inhibitor was more effective if administered during the resting phase of the day, when glucocorticoids are low. These findings support a circadian clock-based paradigm in cancer therapy.
    Type of Publication: Journal article published
    PubMed ID: 25278152
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  • 14
    Keywords: EXPRESSION ; GENE ; FUSION ; PATTERN ; CAVITY
    Abstract: AIMS: Sinonasal haemangiopericytoma (SN-HPC) is a rare sinonasal mesenchymal neoplasm of perivascular myoid cell origin. Solitary fibrous tumour (SFT) occurs only very rarely in the sinonasal tract. SFT and soft tissue HPC have been considered a single entity. Recently, recurrent gene fusions involving NAB2-STAT6 resulting in differential expression of STAT6 were characterized as central molecular events in SFT. However, no data exist for NAB2-STAT6 status or STAT6 expression in SN-HPC. METHODS AND RESULTS: We examined six SN-HPCs and two sinonasal SFTs by immunohistochemistry and RT-PCR for NAB2-STAT6 fusions. SN-HPC affected three females and three males (mean age: 72 years). They expressed smooth muscle actin, lacked strong CD34 reactivity and were negative for nuclear STAT6 expression. RT-PCR analysis confirmed the absence of NAB2-STAT6 fusions in all cases. Conversely, both sinonasal SFTs (in males aged 39 and 52 years) displayed classical features of pleuropulmonary and soft-tissue SFTs (uniformly CD34-positive with strong nuclear expression of STAT6). RT-PCR revealed NAB2-STAT6 fusions in both cases. CONCLUSIONS: These findings confirm the molecular and phenotypical distinctness of these two entities. While SN-HPC is a site-specific sinonasal neoplasm of as yet unknown molecular pathogenesis, sinonasal SFTs show phenotypical and molecular identity to their pleural/extrapleural counterparts.
    Type of Publication: Journal article published
    PubMed ID: 24807787
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  • 15
    Keywords: EXPRESSION ; GENE ; VARIANTS ; FUSION ; BENIGN ; ANNOTATION ; GENOMES ; SOLITARY FIBROUS TUMOR ; DESMOID TUMORS ; FIBROMATOSIS
    Abstract: Sinonasal hemangiopericytoma (SN-HPC) is an uncommon, site-specific, low-grade mesenchymal neoplasm of probable perivascular myoid cell origin. In contrast to solitary fibrous tumors of soft tissue and sinonasal tract origin, SN-HPCs were recently shown to lack recurrent NAB2-STAT6 fusion variants. Other molecular alterations known to occur in some of soft tissue perivascular myoid cell neoplasms were also absent in SN-HPC; thus, the molecular pathogenesis of SN-HPCs remained unknown. Guided by whole-genome sequencing combined with RNA sequencing of an index case, we analyzed a total of six SN-HPCs for mutations within the amino-terminal region of the gene catenin (cadherin-associated protein), beta 1, 88 kDa (CTNNB1), encoding for beta-catenin. All six cases showed missense mutations, with amino acid substitutions clustering at positions 33 to 45, corresponding to the recognition site of the beta-catenin destruction complex. Similar CTNNB1 mutations have been described in a variety of epithelial and mesenchymal neoplasms. These mutations prevent beta-catenin phosphorylation and proteasomal degradation but promote its nuclear accumulation and subsequent increased transcription of Wingless-related integration site target genes. Consistent with these molecular findings, beta-catenin IHC showed consistent diffuse and strong nuclear staining of the tumor cells in all six SN-HPCs. Our results highlight, for the first time, CTNNB1 mutations as the likely initiating molecular events driving SN-HPC tumorigenesis, which places SN-HPC among the growing family of beta-catenin-driven mesenchymal neoplasms.
    Type of Publication: Journal article published
    PubMed ID: 25482924
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  • 16
    Keywords: EXPRESSION ; Germany ; human ; DISEASE ; GENE ; GENE-EXPRESSION ; GENES ; TISSUE ; TISSUES ; LINKAGE ; MOUSE ; IDENTIFICATION ; IN-SITU ; gene expression ; NUMBER ; DATABASE ; REGION ; REGIONS ; LOCALIZATION ; ORGANIZATION ; RE ; EXPRESSION PATTERNS ; MAP ; MENTAL-RETARDATION ; SUBUNIT PROTEIN ; CPG-BINDING PROTEIN-2
    Abstract: Background: Well known for its gene density and the large number of mapped diseases, the human sub-chromosomal region Xq28 has long been a focus of genome research. Over 40 of approximately 300 X-linked diseases map to this region, and systematic mapping, transcript identification, and mutation analysis has led to the identification of causative genes for 26 of these diseases, leaving another 17 diseases mapped to Xq28, where the causative gene is still unknown. To expedite disease gene identification, we have initiated the functional characterisation of all known Xq28 genes. Results: By using a systematic approach, we describe the Xq28 genes by RNA in situ hybridisation and Northern blotting of the mouse orthologs, as well as subcellular localisation and data mining of the human genes. We have developed a relational web-accessible database with comprehensive query options integrating all experimental data. Using this database, we matched gene expression patterns with affected tissues for 16 of the 17 remaining Xq28 linked diseases, where the causative gene is unknown. Conclusion: By using this systematic approach, we have prioritised genes in linkage regions of Xq28-mapped diseases to an amenable number for mutational screens. Our database can be queried by any researcher performing highly specified searches including diseases not listed in OMIM or diseases that might be linked to Xq28 in the future
    Type of Publication: Journal article published
    PubMed ID: 16503986
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  • 17
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; CELL ; Germany ; human ; SYSTEM ; DISEASE ; GENES ; GENOME ; PROTEIN ; PROTEINS ; ACTIVATION ; FLOW ; antibodies ; antibody ; IDENTIFICATION ; ASSAY ; CELL-DEATH ; fragmentation ; HUMAN GENOME ; FLUORESCENCE ; INHIBITORS ; CHEMISTRY ; RE ; flow cytometry ; genomics ; MEDIATED APOPTOSIS ; methods ; NUCLEAR ; USA ; function ; CANDIDATE ; microbiology ; caspase-3 ; cell-based assay ; PERMEABILITY TRANSITION PORE ; VIRUS CORE PROTEIN
    Abstract: After sequencing the human genome, the challenge ahead is to systematically analyze the functions and disease relation of the proteins encoded. Here the authors describe the application of a flow cytometry-based high-throughput assay to screen for apoptosis-activating proteins in transiently transfected cells. The assay is based on the detection of activated caspase-3 with a specific antibody, in cells overexpressing proteins tagged C- or N-terminally with yellow fluorescent protein. Fluorescence intensities are measured using a flow cytometer integrated with a high-throughput autosampler. The applicability of this screen has been tested in a pilot screen with 200 proteins. The candidate proteins were all verified in an independent microscopy-based nuclear fragmentation assay, finally resulting in the identification of 6 apoptosis inducers
    Type of Publication: Journal article published
    PubMed ID: 17478479
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  • 18
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; CELL ; Germany ; INHIBITION ; KINASE ; PATHWAY ; QUANTIFICATION ; SYSTEM ; SYSTEMS ; DISTINCT ; GENOME ; microarray ; PROTEIN ; PROTEINS ; SAMPLE ; SAMPLES ; ACTIVATION ; BIOLOGY ; MOLECULAR-BIOLOGY ; BREAST ; breast cancer ; BREAST-CANCER ; STIMULATION ; microarrays ; ARRAYS ; systems biology ; PROTEOMICS ; EPIDERMAL-GROWTH-FACTOR ; signaling ; molecular biology ; molecular ; RE ; ARRAY ; EGFR ; analysis ; methods ; HIGH-THROUGHPUT ; HER2 ; GEFITINIB ; comparison ; BREAST-CANCER-CELLS ; EGF ; ERK1/2 ; reverse phase protein array ; HER2/neu ; herceptin
    Abstract: Protein microarrays allow highly accurate comparison and quantification of numerous biological samples in parallel while requiring only little material. This qualifies protein arrays for systems biology and clinical research where only limited sample material is available, but a precise read-out is required. With the introduction of signal normalization steps to monitor the drop size of manually contact-spotted RP protein arrays, the usefulness of normalizer proteins to ensure a high-throughput but inexpensive protein analysis was demonstrated. This approach was applied for the analysis of signaling through ERBB receptor activated kinases in the breast cancer cell line MCF-7. Activation of ERK1/2 and AKT by ERBB1 (EGFR), ERRB2 (HER2/neu), and ERBB3-4 was monitored in a time-resolved manner. Analysis of pathway activation by stimulation with epidermal growth factor and heregulin, or inhibition by blocking with gefitinib or herceptin allowed a characterization of the distinct signaling properties of the different ERBB receptor subtypes
    Type of Publication: Journal article published
    PubMed ID: 18351692
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  • 19
    Keywords: EXPRESSION ; COMBINATION ; SYSTEM ; SYSTEMS ; GENE ; GENE-EXPRESSION ; GENOME ; microarray ; COMPLEX ; MEMBERS ; EXPERIENCE ; gene expression ; MICROARRAY DATA ; ASSAY ; genetics ; DATABASE ; OUTCOMES ; heredity ; PROTEOMICS ; MANAGEMENT ; genomics ; TECHNOLOGY ; USA ; microbiology ; ENGLAND ; biotechnology ; CONSORTIUM ; UK ; DATA STANDARDS ; MINIMUM INFORMATION
    Abstract: This article summarizes the motivation for, and the proceedings of, the first ISA-TAB workshop held December 6-8, 2007, at the EBI, Cambridge, UK. This exploratory workshop, organized by members of the Microarray Gene Expression Data (MGED) Society's Reporting Structure for Biological Investigations (RSBI) working group, brought together a group of developers of a range of collaborative systems to discuss the use of a common format to address the pressing need of reporting and communicating data and metadata from biological, biomedical, and environmental studies employing combinations of genomics, transcriptomics, proteomics, and metabolomics technologies along with more conventional methodologies. The expertise of the participants comprised database development, data management, and hands-on experience in the development of data communication standards. The workshop's outcomes are set to help formalize the proposed Investigation, Study, Assay (ISA)-TAB tab-delimited format for representing and communicating experimental metadata. This article is part of the special issue of OMICS on the activities of the Genomics Standards Consortium (GSC)
    Type of Publication: Journal article published
    PubMed ID: 18447634
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  • 20
    Keywords: EXPRESSION ; LINES ; DYNAMICS ; breast cancer ; REQUIRES ; SERUM RESPONSE FACTOR ; EPITHELIAL-MESENCHYMAL TRANSITION ; miR-200 family ; FORMIN ; FIBER FORMATION ; ZEB1
    Abstract: MicroRNA-200c (miR-200c) has been shown to suppress epithelial-to-mesenchymal transition (EMT), which is mainly attributed to targeting of ZEB1/ZEB2, repressors of the cell-cell contact protein E-Cadherin. Here, we demonstrated that modulation of miR-200c in breast cancer cells regulates cell migration, cell elongation and TGF-beta-induced stress fiber formation, by impacting the re-organization of cytoskeleton that is independent of the ZEB/E-Cadherin-axis. We identified FHOD1 and PPM1F, direct regulators of the actin cytoskeleton, as novel targets of miR-200c. Remarkably, expression levels of FHOD1 and PPM1F were inversely correlated with miR-200c in breast cancer cell lines, breast cancer patient samples, as well as in 58 cancer cell lines of various origin. Furthermore, individual knockdown/overexpression of these target genes phenocopied the effects of miR-200c overexpression/inhibition on cell elongation, stress fiber formation, migration and invasion. Mechanistically, targeting of FHOD1 by miR-200c resulted in decreased expression and transcriptional activity of SRF mediated by interference with the translocation of SRF co-activator MRTF-A. This finally led to downregulation of the expression and phosphorylation of the SRF target gene MLC2 required for stress fiber formation and contractility. Thus, miR-200c impacts on metastasis by regulating several EMT-related processes, including a novel mechanism involving the direct targeting of actin-regulatory proteins.
    Type of Publication: Journal article published
    PubMed ID: 22144583
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