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  • 1
    Keywords: GENE-EXPRESSION ; DIFFERENTIATION ; TUMORS ; BIOLOGY ; PROGRESSION ; PHENOTYPE ; P-TEFB ; RISK STRATIFICATION ; SUBGROUPS ; MIRNA EXPRESSION
    Abstract: Neuroblastoma, a childhood cancer that originates from neural crest-derived cells, is the most common deadly solid tumor of infancy. Amplification of the MYCN oncogene, which occurs in approximately 20-25% of human neuroblastomas, is the most prominent genetic marker of high-stage disease. The availability of valid preclinical in vivo models is a prerequisite to develop novel targeted therapies. We here report on the generation of transgenic mice with Cre-conditional induction of MYCN in dopamine beta-hydroxylase-expressing cells, termed LSL-MYCN;Dbh-iCre. These mice develop neuroblastic tumors with an incidence of 〉75%, regardless of strain background. Molecular profiling of tumors revealed upregulation of the MYCN-dependent miR-17-92 cluster as well as expression of neuroblastoma marker genes, including tyrosine hydroxylase and the neural cell adhesion molecule 1. Gene set enrichment analyses demonstrated significant correlation with MYC-associated expression patterns. Array comparative genome hybridization showed that chromosomal aberrations in LSL-MYCN;Dbh-iCre tumors were syntenic to those observed in human neuroblastomas. Treatment of a cell line established from a tumor derived from a LSL-MYCN;Dbh-iCre mouse with JQ1 or MLN8237 reduced cell viability and demonstrated oncogene addiction to MYCN. Here we report establishment of the first Cre-conditional human MYCN-driven mouse model for neuroblastoma that closely recapitulates the human disease with respect to tumor localization, histology, marker expression and genomic make up. This mouse model is a valuable tool for further functional studies and to assess the effect of targeted therapies.Oncogene advance online publication, 1 September 2014; doi:10.1038/onc.2014.269.
    Type of Publication: Journal article published
    PubMed ID: 25174395
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  • 2
    Keywords: APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; INHIBITOR ; tumor ; TUMOR-CELLS ; CELL ; Germany ; human ; IN-VIVO ; INHIBITION ; DEATH ; GENE ; GENE-EXPRESSION ; RNA ; TUMORS ; ACTIVATION ; PROTEIN FAMILY ; INDUCTION ; SUSCEPTIBILITY ; TARGET ; gene expression ; resistance ; HUMAN-TUMORS ; STIMULI ; CANCER-CELLS ; DELIVERY ; MAMMALIAN-CELLS ; SMALL INTERFERING RNAS ; doxorubicin ; HUMAN-TUMOR-CELLS ; IAP PROTEINS ; POSITIVE CANCER-CELLS ; RNA interference,inhibitors of apoptosis,chemotherapy,HeLa,melanoma ; STRATEGIES
    Abstract: Increased resistance to apoptosis is a hallmark of many tumor cells. The functional inhibition of specific antiapoptotic factors may provide a rational basis for the development of novel therapeutic strategies. We investigated here whether the RNA interference (RNAi) technology could be used to increase the apoptotic susceptibility of cancer cells. As a molecular target, we chose the antiapoptotic livin (ML-IAP, KIAP) gene, which is expressed in a subset of human tumors. We identified vector-borne small interfering (si)RNAs, which could efficiently block endogenous livin gene expression. Silencing of livin was associated with caspase-3 activation and a strongly increased apoptotic rate in response to different proapoptotic stimuli, such as doxorubicin, UV-irradiation, or TNFalpha. The effects were specific for Livin-expressing tumor cells. Our results (i) provide direct evidence that the intracellular interference with livin gene expression resensitizes human tumor cells to apoptosis, (ii) define the livin gene as a promising molecular target for therapeutic inhibition, and (iii) show that the livin gene is susceptible to efficient and specific silencing by the siRNA technology
    Type of Publication: Journal article published
    PubMed ID: 14614456
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  • 3
    Keywords: CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; CELL ; Germany ; human ; DISEASE ; CDNA ; GENE ; GENE-EXPRESSION ; GENES ; PATIENT ; NF-KAPPA-B ; ACTIVATION ; PHOSPHORYLATION ; treatment ; gene expression ; PCR ; CANCER-CELLS ; PRODUCT ; max ; REGULATOR ; HIGH-LEVEL ; GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE ; REDUCTASE ; BIOLOGICAL-ACTIVITIES ; CEREBELLAR NEURONS ; CHROMOSOMAL INSTABILITY ; Fanconi anemia,GAPDH,redox potential,thioredoxin ; REDOX REGULATION
    Abstract: Cancer cells have high levels of thioredoxin ( Trx) and of glyceraldehyde 3- phosphate dehydrogenase ( GAPDH). Cells from patients with the cancer- prone disease Fanconi anemia ( FA) exhibit reduced Trx levels. We found the activity of GAPDH to correlate directly with the endogenous Trx content and mRNA transcripts for GAPDH and TRx reduced in FA cells. The treatment of cells with reduced human Trx stimulated the synthesis of GAPDH mRNA. Similarly, the transfection of cells with an expression plasmid for Trx increased GAPDH mRNA synthesis. Trx treatment of cells and subsequent analysis of the differential gene expression by human cDNA arrays containing about 50 000 different PCR products resulted in more than 300 up- or downregulated genes. Two representative genes, GAPDH and IkappaBalpha/ MAD- 3, were further investigated to confirm their stimulation by Trx. Trx besides being the major carrier of redox potential of cells is also a regulator of gene expression on the transcriptional level. By regulation via Trx, cells are able to adapt to the prevailing redox conditions. These findings also enlighten the pathophysiology of FA in the respect that the characteristic diminution of Trx that results in the dysregulation of gene expression is a basis for the major symptoms of this disease
    Type of Publication: Journal article published
    PubMed ID: 14730345
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  • 4
    Keywords: CANCER ; CELLS ; EXPRESSION ; tumor ; CELL ; GENE ; GENES ; cell line ; TUMORS ; DNA ; CYCLE ; AMPLIFICATION ; CELL-LINE ; LINE ; p53 ; DAMAGE ; INSTABILITY ; DNA-DAMAGE ; DUPLICATION ; ABNORMALITIES ; OVEREXPRESSION ; GENETIC INSTABILITY ; N-MYC ; micronuclei ; CHROMOSOME INSTABILITY ; MYCN,centrosome,micronuclei,DNA damage ; OVERDUPLICATION
    Abstract: Centrosomes play important roles in cell polarity, regulation of cell cycle and chromosomal stability. Centrosome abnormality is frequently found in many cancers and contributes to chromosomal instability (including aneuploidy, tetraploidy, and/or micronuclei) in daughter cells through the assembly of multipolar or monopolar spindles during mitosis. It has recently been reported that loss of tumor suppressor genes or overexpression of oncogenes causes centrosome hyperamplification. Amplification and overexpression of the MYCN oncogene is found in a subgroup of neuroblastomas. In this study, we examined whether overexpression of MYCN causes centrosome hyperamplification in neuroblastoma cells. We show that ectopic expression of MYCN alone in a neuroblastoma cell line did not cause centrosome hyperamplification. However, centrosome hyperamplification and micronuclei formation were seen in these cells after DNA damage. These findings suggest that overexpression of MYCN abrogates the regulation of the centrosome cycle after DNA damage
    Type of Publication: Journal article published
    PubMed ID: 14647433
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  • 5
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; Germany ; KINASE ; GENE ; GENE-EXPRESSION ; PROTEIN ; DIFFERENTIATION ; TRANSDUCTION ; ACTIVATION ; COMPLEX ; COMPLEXES ; MECHANISM ; MESSENGER-RNA ; DOMAIN ; mechanisms ; DOWN-REGULATION ; PHOSPHORYLATION ; PROTEIN-KINASE ; signal transduction ; ALPHA ; BREAST ; breast cancer ; BREAST-CANCER ; hormone ; gene expression ; TRANSCRIPTIONAL ACTIVITY ; SIGNAL-TRANSDUCTION ; CANCER-CELLS ; CARCINOMA-CELLS ; LOCALIZATION ; PROTEIN-KINASE-C ; PHORBOL ESTER ; ESTRADIOL ; SYNTHASE ; TRANSFECTION ; regulation ; ESTROGEN ; estrogen receptor ; GLYCOGEN-SYNTHASE KINASE-3 ; GSK3 ; MCF-7 CELLS ; PKC ; PKC delta
    Abstract: Regulation of estrogen receptor (ER) function in breast cancer cells is a complex process involving different signalling mechanisms. One signal transduction component that appears to influence ER signalling is protein kinase C (PKC). PKC delta is a particular isoenzyme of the novel PKC subfamily that plays a role in growth control, differentiation and apoptosis. The aim of the present study was to investigate the impact of PKC delta on the regulation of the transcriptional activity of the human ER alpha. By using 12-O-tetradecanoylphorbol- 13-acetate (TPA), Bryostatin1 and Rottlerin, we show that active PKC delta is a proproliferative factor in estrogen-dependent breast cancer cells. Furthermore, activation of PKC delta by TPA resulted in activation and nuclear translocation of ER alpha and in an increase of ER-dependent reporter gene expression. Transfection and expression of the regulatory domain RD delta of PKC delta, which is inhibitory to PKC delta, inhibited the TPA-induced ER alpha activation and translocation. ER alpha was not phosphorylated by PKC delta; however, glycogen synthase kinase-3 (GSK3) was identified as a substrate of PKC delta. The expression of RD delta resulted in a decrease of TPA-induced GSK3 phosphorylation and translocation into the nucleus. We suggest that GSK3 plays a role in the PKC delta-related nuclear translocation of ER alpha
    Type of Publication: Journal article published
    PubMed ID: 15824731
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  • 6
    Keywords: RECEPTOR ; EXPRESSION ; Germany ; KINASE ; TYROSINE KINASE ; GENE ; GENE-EXPRESSION ; GENES ; transcription ; ACCURACY ; TRANSDUCTION ; PATIENT ; ACTIVATION ; DOMAIN ; cell cycle ; CELL-CYCLE ; CYCLE ; signal transduction ; IDENTIFICATION ; PATTERNS ; gene expression ; MUTATION ; SIGNAL-TRANSDUCTION ; leukemia ; REGION ; MUTATIONS ; PROGNOSTIC-SIGNIFICANCE ; CONSTITUTIVE ACTIVATION ; SERIES ; point mutation ; gene expression profiling ; CYCLE CONTROL ; HEMATOLOGIC MALIGNANCIES ; GENE-MUTATIONS ; ACUTE MYELOGENOUS LEUKEMIA ; acute myeloid leukemia ; NORMAL CYTOGENETICS ; STUDY-GROUP ULM ; CANDIDATE GENES ; INTERNAL TANDEM DUPLICATION ; MYELOID-LEUKEMIA ; GENE-TRANSCRIPTION ; ADULT PATIENTS ; HIGH-DOSE CYTARABINE ; EXPRESSION PATTERNS ; SIGNATURE ; COOPERATIVE-GROUP ; FLT3-activating mutations ; normal karyotype ; NRAS-activating mutations ; SONIC-HEDGEHOG
    Abstract: In acute myeloid leukemia (AML), constitutive activation of the FLT3 receptor tyrosine kinase, either by internal tandem duplications (FLT3-ITD) of the juxtamembrane region or by point mutations in the second tyrosine kinase domain (FLT3-TKD), as well as point mutations of the NRAS gene (NRAS-PM) are among the most frequent somatic gene mutations. To elucidate whether these mutations cause aberrant signal transduction in AML, we used gene expression pro. ling in a series of 110 newly diagnosed AML patients with normal karyotype. The different algorithms used for data analysis revealed highly concordant sets of genes, indicating that the identified gene signatures are specific for each analysed subgroup. Whereas samples with FLT3-ITD and FLT3-TKD could be separated with up to 100% accuracy, this did not apply for NRAS-PM and wild-type samples, suggesting that only FLT3-ITD and FLT3-TKD are associated with an apparent signature in AML. The set of discriminating genes included several known genes, which are involved in cell cycle control (CDC14A, WEE1), gene transcription (HOXB5, FOXA1), and signal transduction (SMG1). In conclusion, we showed that unique gene expression patterns can be correlated with FLT3-ITD and FLT3-TKD. This might lead to the identification of further pathogenetic relevant candidate genes particularly in AML with normal karyotype
    Type of Publication: Journal article published
    PubMed ID: 15674343
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  • 7
    Keywords: CANCER ; EXPRESSION ; Germany ; GENE ; PROTEIN ; PROTEINS ; transcription ; TISSUE ; SURGERY ; LINES ; PATIENT ; COMPLEX ; DOMAIN ; tumour ; CELL-LINES ; SEQUENCE ; PROGRESSION ; ASSAY ; Drosophila ; colorectal cancer ; COLORECTAL-CANCER ; metastases ; LINE ; REGION ; MUTATIONS ; ADHESION ; MIGRATION ; cytoskeleton ; POLYMERASE-CHAIN-REACTION ; cell lines ; CELL-MIGRATION ; BINDS ; CELL POLARITY ; MAPS ; colon cancer ; TUMORIGENESIS ; cell adhesion ; cell migration ; ASSAYS ; SUPPRESSOR ; tumour suppressor ; APC ; 17P11.2 ; Hugl-1 ; II HEAVY-CHAIN ; LETHAL-GIANT-LARVAE ; lgl
    Abstract: The human gene, human giant larvae (Hugl-1/Llg1/Lgl1) has significant homology to the Drosophila tumour suppressor gene lethal( 2) giant larvae (lgl). The lgl gene codes for a cortical cytoskeleton protein, Lgl, that binds Myosin II and is involved in maintaining cell polarity and epithelial integrity. The human protein, Hugl-1 contains several conserved functional domains found in Lgl, suggesting that these proteins may have closely related functions. Whether loss of Hugl expression plays a role in human tumorigenesis has so far not been extensively investigated. Thus, we evaluated tumour tissues from 94 patients undergoing surgery for colorectal cancer (CRC) for loss of Hugl-1 transcription and compared our findings with the clinical data from each of these patients. We found that Hugl-1 was lost in 75% of tumour samples and these losses were associated with advanced stage and particularly with lymph node metastases. Reduced Hugl-1 expression during the adenoma-carcinoma sequence occurring as early as in colorectal adenomas was detected by both immunohistochemical and reverse transcription polymerase chain reaction analysis. Functional assays with ecdysone-inducible cell lines revealed that Hugl-1 expression increased cell adhesion and decreased cell migration. Our studies thus indicate that downregulation of Hugl-1 contributes to CRC progression
    Type of Publication: Journal article published
    PubMed ID: 15735678
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  • 8
    Keywords: RECEPTOR ; ANGIOGENESIS ; CELLS ; EXPRESSION ; INHIBITOR ; INVASION ; SURVIVAL ; tumor ; Germany ; KINASE ; THERAPY ; TYROSINE KINASE ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; TUMORS ; TIME ; ACTIVATION ; FAMILY ; BIOLOGY ; NERVOUS-SYSTEM ; PATTERNS ; gene expression ; microarrays ; resistance ; LINE ; SIGNALING PATHWAYS ; LIGANDS ; PHENOTYPE ; CHILDREN ; RECEPTORS ; MICROARRAY ANALYSIS ; expression profiling ; PROGNOSTIC FACTOR ; neuroblastoma ; GROWTH-FACTOR-II ; INHIBITORS ; ABSENCE ; SINGLE ; PROGRAM ; OLIGONUCLEOTIDE ; SOLID TUMORS ; regulation ; PROGNOSTIC-FACTOR ; GENE-REGULATION ; NEUROTROPHIC FACTOR ; TARGET GENE ; gene regulation ; TARGET GENES ; PROFILES ; EXPRESSION PATTERNS ; EXPRESSION PROFILES ; HIGH EXPRESSION ; CYTOTOXIC DRUGS ; FACTOR BINDING-PROTEINS ; Trk receptors
    Abstract: Expression of neurotrophin receptors of the tyrosine kinase receptor (Trk) family is an important prognostic factor in solid tumors including neuroblastoma. High expression of TrkA (NTRK1) is associated with a favorable biology and outcome of neuroblastoma, whereas TrkB (NTRK2) is expressed on aggressive neuroblastomas with unfavorable outcome. To gain new insights into the global gene expression program resulting in these divergent biological phenotypes, we stably expressed either TrkA or TrkB in the human SH-SY5Y neuroblastoma cell line. Gene expression profiles were obtained from parental cells and transfectants activated by their ligands in a time course over 24 h using oligonucleotide microarrays. Basal activation of Trk receptors in the absence of exogenous ligand was sufficient to induce broad and divergent genetic changes. Global gene regulation following external ligand stimulation was surprisingly similar in SY5Y-TrkA and SY5Y-TrkB cells except for the differential expression of distinct novel target genes. Consistent with their divergent biological phenotype, SY5Y-TrkA cells were characterized by upregulation of proapoptotic genes and angiogenesis inhibitors, whereas SY5Y-TrkB cells demonstrated upregulation of genes involved in invasion or therapy resistance. We suggest that the transcriptional program of neuroblastoma cells is modulated by Trk-receptor expression and basal activation rather than by ligand-induced activation. Fine-tuning of the malignant phenotype may be achieved by additional ligand stimulation with subsequent activation of a few specific genes
    Type of Publication: Journal article published
    PubMed ID: 15637590
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  • 9
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; proliferation ; tumor ; carcinoma ; Germany ; human ; IN-VIVO ; VITRO ; VIVO ; SITE ; SITES ; GENE ; HYBRIDIZATION ; PROTEIN ; DIFFERENTIATION ; TISSUE ; TUMORS ; PATIENT ; CARCINOGENESIS ; KERATINOCYTES ; SKIN ; IN-SITU ; PROGRESSION ; AMPLIFICATION ; COMPARATIVE GENOMIC HYBRIDIZATION ; immunohistochemistry ; CHROMOSOMAL-ABERRATIONS ; skin carcinogenesis ; LOCALIZATION ; PHENOTYPE ; SQUAMOUS-CELL CARCINOMA ; CARCINOMAS ; squamous cell carcinoma ; p21 ; NONMELANOMA SKIN CANCERS ; FLUORESCENCE ; OVEREXPRESSION ; ORGANIZATION ; TERMINAL DIFFERENTIATION ; P53 MUTATIONS ; SKIN-CANCER ; CYCLIN D1 ; in situ hybridization ; CELL CARCINOMA ; REGRESSION ; RE ; TUMORIGENICITY ; CANCER DEVELOPMENT ; LOCUS ; function ; CANCERS ; in vivo ; genomic ; aberrant differentiation ; cdk4 ; KERATINOCYTES HACAT ; keratoacanthoma ; nonmelanoma skin cancer ; ORGANOTYPIC COCULTURE ; tumor regression
    Abstract: Non-melanoma skin cancers, in particular keratoacanthomas (KAs) and squamous cell carcinomas (SCCs), have become highly frequent tumor types especially in immune-suppressed transplant patients. Nevertheless, little is known about essential genetic changes. As a paradigm of 'early' changes, that is, changes still compatible with tumor regression, we studied KAs by comparative genomic hybridization and show that gain of chromosome 11q is not only one of the most frequent aberration (8/18), but in four tumors also the only aberration. Furthermore, 11q gain correlated with amplification of the cyclin D1 locus (10/14), as determined by fluorescence in situ hybridization, and overexpression of cyclin D1 protein (25/31), as detected by immunohistochemistry. For unraveling the functional consequence, we overexpressed cyclin D1 in HaCaT skin keratinocytes. These cells only gained little growth advantage in conventional and in organotypic cocultures. However, although the control vector-transfected cells formed a well-stratified and orderly differentiated epidermis-like epithelium, they showed deregulation of tissue architecture with an altered localization of proliferation and impaired differentiation. The most severe phenotype was seen in a clone that additionally upregulated cdk4 and p21. These cells lacked terminal differentiation, exhibited a more autonomous growth in vitro and in vivo and even formed tumors in two injection sites with a growth pattern resembling that of human KAs. Thus, our results identify 11q13 gain/cyclin D1 overexpression as an important step in KA formation and point to a function that exceeds its known role in proliferation by disrupting tissue organization and thereby allowing abnormal growth
    Type of Publication: Journal article published
    PubMed ID: 16547504
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  • 10
    Keywords: RECEPTOR ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; carcinoma ; CELL ; GENE ; GENES ; ACTIVATION ; MECHANISM ; CONTRAST ; mechanisms ; SEQUENCE ; SEQUENCES ; ALPHA ; ACID ; gene expression ; PROMOTER ; prostate cancer ; oligonucleotides ; CANCER-CELLS ; CARCINOMA-CELLS ; EPITHELIAL-CELLS ; FATTY-ACIDS ; adenocarcinoma ; PPAR-GAMMA ; BINDING PROTEIN ; PROSTATE-CANCER CELLS ; gene regulation ; FRAGMENT ; ANDROGEN ; NUCLEAR RECEPTOR ; 15-lipoxygenase-2 ; peroxisome proliferator-activated receptor gamma ; ROR-ALPHA
    Abstract: An inverse relationship exists between the expression of 15-lipoxygenase-2 (15-LOX-2) and peroxisome proliferator-activated receptor c (PPARc) in normal prostate epithelial cells (PrECs) compared with their expression in prostate carcinoma cells (PC-3). The reason for this difference, however, is unknown. We hypothesized that this inverse expression partly involves the 15-LOX-2 promoter and 15-S-hydroxyeicosatetraenoic acid (15-(S)HETE), a product of 15- LOX-2 that binds to PPARc. We identified an active steroid nuclear receptor half-site present in the 15-LOX-2 promoter fragment F-5 (-618/+177) that can interact with PPARc. After forced expression of wild-type PPARc, 15-(S)-HETE (1 mu M) decreased F-5 reporter activity in PrECs whereas forced expression of 15-LOX-2 resulted in 15-(S)-HETE production which enhanced F-5 activity in PC-3. In contrast, the expression of dominant-negative PPARc reversed the transcriptional activation of F-5 by enhancing it 202-fold in PrEC or suppressing it in PC-3; the effect in PC-3 was positively increased 150-fold in the presence of 15-(S)-HETE (1 mu M). Peroxisome proliferator-activated receptor c interacted with 15-LOX-2 promoter sequences in pulldown experiments using biotinylated 15-LOX-2 (-560/-596 bp) oligonucleotides. In gelshift analyses PPARc and orphan receptor ROR alpha were shown to interact with the F-5 fragment in PC-3 cells. These data suggest that crosstalk mechanisms exist between the 15-LOX-2 gene and PPARc to counterbalance expression and help explain the inverse relationship of these genes in normal versus cancer cells
    Type of Publication: Journal article published
    PubMed ID: 16682954
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