Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Keywords: CANCER ; EXPRESSION ; GROWTH ; tumor ; CELL ; MODEL ; PATHWAY ; PATHWAYS ; COHORT ; DISEASE ; GENE ; GENE-EXPRESSION ; RNA ; DIFFERENTIATION ; TUMORS ; ACTIVATION ; BINDING ; BIOLOGY ; TARGET ; CHROMATIN ; gene expression ; PROMOTER ; genetics ; MODULATION ; C-MYC ; REPRESSION ; TRANSCRIPTIONAL REPRESSION ; MYCN ; neuroblastoma ; N-MYC ; signaling ; ONCOLOGY ; B-CELL LYMPHOMAS ; miRNA ; outcome ; MICRORNA ; CELL BIOLOGY ; Genetic ; COHORTS ; EXPRESSION SIGNATURES ; PATHWAY DEREGULATION
    Abstract: Increased activity of MYC protein-family members is a common feature in many cancers. Using neuroblastoma as a tumor model, we established a microRNA (miRNA) signature for activated MYCN/c-MYC signaling in two independent primary neuroblastoma tumor cohorts and provide evidence that c-MYC and MYCN have overlapping functions. On the basis of an integrated approach including miRNA and messenger RNA (mRNA) gene expression data we show that miRNA activation contributes to widespread mRNA repression, both in c-MYC- and MYCN-activated tumors. c-MYC/MYCN-induced miRNA activation was shown to be dependent on c-MYC/MYCN promoter binding as evidenced by chromatin immunoprecipitation. Finally, we show that pathways, repressed through c-MYC/MYCN miRNA activation, are highly correlated to tumor aggressiveness and are conserved across different tumor entities suggesting that c-MYC/MYCN activate a core set of miRNAs for cooperative repression of common transcriptional programs related to disease aggressiveness. Our results uncover a widespread correlation between miRNA activation and c-MYC/MYCN-mediated coding gene expression modulation and further substantiate the overlapping functions of c-MYC and MYCN in the process of tumorigenesis. Oncogene (2010) 29, 1394-1404; doi:10.1038/onc.2009.429; published online 30 November 2009
    Type of Publication: Journal article published
    PubMed ID: 19946337
    Signatur Availability
    BibTip Others were also interested in ...
  • 2
    Keywords: EXPRESSION ; GENE ; CELL-CYCLE ; DOWN-REGULATION ; TARGET ; PROSTATE-CANCER ; beta-catenin ; N-MYC ; RNA INTERFERENCE ; REIC/DKK-3
    Abstract: Neuroblastoma (NB) is a paediatric tumour with a remarkable diverse clinical behaviour. Approximately half of the high stage aggressive tumours are characterized by MYCN gene amplification but our understanding of the role of MYCN in NB oncogenesis is incomplete. Previous studies have shown that MYCN expression is inversely correlated with expression of Dickkopf-3 (DKK3), a gene encoding an extracellular protein with presumed tumour suppressor activity, but direct MYCN regulation of DKK3 was excluded leaving the mechanism of regulation unexplained. Given the recently established role of MYCN-regulated miRNAs in downregulation of protein-coding genes and predicted seeds for miR-17-92 cluster members within the DKK3 3'UTR, we hypothesized that this mechanism would act in MYCN regulation of DKK3. To investigate this, we used a validated miR-17-92-inducible cellular system and could demonstrate robust downregulation of DKK3 mRNA and protein levels upon miR-17-92 overexpression. Next, two of the three predicted miRNAs, miR-19b and miR-92a, were shown to lower DKK3 protein levels, in addition to measurable DKK3 mRNA knock-down by miR-92a. Direct interaction between miR-19b or miR-92a and the 3'UTR of DKK3 was validated using luciferase reporter assays. In conclusion, this study demonstrates that the MYCN-induced downregulation of DKK3 results from direct upregulation of miR-17-92 components effecting both DKK3 mRNA stability and translation which further contributes to the pleiotropic oncogenic effect of elevated MYCN levels. The strict MYCN-mediated regulation of DKK3 is suggestive for an important downstream function of the MYCN protein and thus warrants further investigations to unravel the role of DKK3 in NB.
    Type of Publication: Journal article published
    PubMed ID: 21796614
    Signatur Availability
    BibTip Others were also interested in ...
  • 3
    Abstract: Identifying relevant signatures for clinical patient outcome is a fundamental task in high-throughput studies. Signatures, composed of features such as mRNAs, miRNAs, SNPs or other molecular variables, are often non-overlapping, even though they have been identified from similar experiments considering samples with the same type of disease. The lack of a consensus is mostly due to the fact that sample sizes are far smaller than the numbers of candidate features to be considered, and therefore signature selection suffers from large variation. We propose a robust signature selection method that enhances the selection stability of penalized regression algorithms for predicting survival risk. Our method is based on an aggregation of multiple, possibly unstable, signatures obtained with the preconditioned lasso algorithm applied to random (internal) subsamples of a given cohort data, where the aggregated signature is shrunken by a simple thresholding strategy. The resulting method, RS-PL, is conceptually simple and easy to apply, relying on parameters automatically tuned by cross validation. Robust signature selection using RS-PL operates within an (external) subsampling framework to estimate the selection probabilities of features in multiple trials of RS-PL. These probabilities are used for identifying reliable features to be included in a signature. Our method was evaluated on microarray data sets from neuroblastoma, lung adenocarcinoma, and breast cancer patients, extracting robust and relevant signatures for predicting survival risk. Signatures obtained by our method achieved high prediction performance and robustness, consistently over the three data sets. Genes with high selection probability in our robust signatures have been reported as cancer-relevant. The ordering of predictor coefficients associated with signatures was well-preserved across multiple trials of RS-PL, demonstrating the capability of our method for identifying a transferable consensus signature. The software is available as an R package rsig at CRAN (http://cran.r-project.org).
    Type of Publication: Journal article published
    PubMed ID: 25295525
    Signatur Availability
    BibTip Others were also interested in ...
  • 4
    Keywords: APOPTOSIS ; CANCER ; GROWTH ; GENE-EXPRESSION ; STEM-CELLS ; CENTRAL-NERVOUS-SYSTEM ; neuroblastoma ; N-MYC ; BRAIN-TUMORS ; TUMOR-SUPPRESSOR
    Abstract: Previous studies have evaluated the role of miRNAs in cancer initiation and progression. MiR-34a was found to be downregulated in several tumors, including medulloblastomas. Here we employed targeted transgenesis to analyze the function of miR-34a in vivo. We generated mice with a constitutive deletion of the miR-34a gene. These mice were devoid of mir-34a expression in all analyzed tissues, but were viable and fertile. A comprehensive standardized phenotypic analysis including more than 300 single parameters revealed no apparent phenotype. Analysis of miR-34a expression in human medulloblastomas and medulloblastoma cell lines revealed significantly lower levels than in normal human cerebellum. Re-expression of miR-34a in human medulloblastoma cells reduced cell viability and proliferation, induced apoptosis and downregulated the miR-34a target genes, MYCN and SIRT1. Activation of the Shh pathway by targeting SmoA1 transgene overexpression causes medulloblastoma in mice, which is dependent on the presence and upregulation of Mycn. Analysis of miR-34a in medulloblastomas derived from ND2:SmoA1(tg) mice revealed significant suppression of miR-34a compared to normal cerebellum. Tumor incidence was significantly increased and tumor formation was significantly accelerated in mice transgenic for SmoA1 and lacking miR-34a. Interestingly, Mycn and Sirt1 were strongly expressed in medulloblastomas derived from these mice. We here demonstrate that miR-34a is dispensable for normal development, but that its loss accelerates medulloblastomagenesis. Strategies aiming to re-express miR-34a in tumors could, therefore, represent an efficient therapeutic option. (c) 2014 Wiley Periodicals, Inc.
    Type of Publication: Journal article published
    PubMed ID: 25348795
    Signatur Availability
    BibTip Others were also interested in ...
  • 5
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; ONCOGENE ; MYCN ; CHROMOSOME 1P ; MicroRNAs ; AURORA-B ; YM155
    Abstract: MicroRNAs (miRNAs) are deregulated in a variety of human cancers, including neuroblastoma, the most common extracranial tumor of childhood. We previously reported a signature of 42 miRNAs to be highly predictive of neuroblastoma outcome. One miRNA in this signature, miR-542, was downregulated in tumors from patients with adverse outcome. Reanalysis of quantitative PCR and next-generation sequencing transcript data revealed that miR-542-5p as well as miR-542-3p expression is inversely correlated with poor prognosis in neuroblastoma patients. We, therefore, analyzed the function of miR-542 in neuroblastoma tumor biology. Ectopic expression of miR-542-3p in neuroblastoma cell lines reduced cell viability and proliferation, induced apoptosis and downregulated Survivin. Survivin expression was also inversely correlated with miR-542-3p expression in primary neuroblastomas. Reporter assays confirmed that miR-542-3p directly targeted Survivin. Downregulating Survivin using siRNA copied the phenotype of miR-542-3p expression in neuroblastoma cell lines, while cDNA-mediated ectopic expression of Survivin partially rescued the phenotype induced by miR-542-3p expression. Treating nude mice bearing neuroblastoma xenografts with miR-542-3p-loaded nanoparticles repressed Survivin expression, decreased cell proliferation and induced apoptosis in the respective xenograft tumors. We conclude that miR-542-3p exerts its tumor suppressive function in neuroblastoma, at least in part, by targeting Survivin. Expression of miR-542-3p could be a promising therapeutic strategy for treating aggressive neuroblastoma.
    Type of Publication: Journal article published
    PubMed ID: 25046253
    Signatur Availability
    BibTip Others were also interested in ...
  • 6
    Keywords: CANCER ; EXPRESSION ; GENE ; transcription ; DIFFERENTIATION ; AMPLIFICATION ; ONCOGENE ; REVEALS ; genomics ; MicroRNAs
    Abstract: MYCN is a transcription factor that plays key roles in both normal development and cancer. In neuroblastoma, MYCN acts as a major oncogenic driver through pleiotropic effects regulated by multiple protein encoding genes as well as microRNAs (miRNAs). MYCN activity is tightly controlled at the level of transcription and protein stability through various mechanisms. Like most genes, MYCN is further controlled by miRNAs, but the full complement of all miRNAs implicated in this process has not been determined through an unbiased approach. To elucidate the role of miRNAs in regulation of MYCN, we thus explored the MYCN-miRNA interactome to establish miRNAs controlling MYCN expression levels. We combined results from an unbiased and genome-wide high-throughput miRNA target reporter screen with miRNA and mRNA expression data from patients and a murine neuroblastoma progression model. We identified 29 miRNAs targeting MYCN, of which 12 miRNAs are inversely correlated with MYCN expression or activity in neuroblastoma tumor tissue. The majority of MYCN-targeting miRNAs in neuroblastoma showed a decrease in expression during murine MYCN-driven neuroblastoma tumor development. Therefore, we provide evidence that MYCN-targeting miRNAs are preferentially downregulated in MYCN-driven neuroblastoma, suggesting that MYCN negatively controls the expression of these miRNAs, to safeguard its expression.
    Type of Publication: Journal article published
    PubMed ID: 25294817
    Signatur Availability
    BibTip Others were also interested in ...
  • 7
    Keywords: ANGIOGENESIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; INVASION ; PATHWAY ; GENE ; PROTEIN ; RNA ; MICE ; ACTIVATION ; BREAST ; breast cancer ; BREAST-CANCER ; TARGET ; PROGRESSION ; AMPLIFICATION ; METASTASIS ; CANCER-CELLS ; ADHESION ; STEM-CELLS ; beta-catenin ; TARGETS ; C-MYC ; OVEREXPRESSION ; TUMOR ANGIOGENESIS ; MAMMARY EPITHELIAL-CELLS ; N-MYC ; HUMAN BREAST-CANCER ; E-cadherin ; MOTILITY ; miRNA ; MESENCHYMAL TRANSITION ; CELL BIOLOGY
    Abstract: MicroRNAs (miRNAs) are increasingly implicated in regulating the malignant progression of cancer. Here we show that miR-9, which is upregulated in breast cancer cells, directly targets CDH1, the E-cadherin-encoding messenger RNA, leading to increased cell motility and invasiveness. miR-9-mediated E-cadherin downregulation results in the activation of beta-catenin signalling, which contributes to upregulated expression of the gene encoding vascular endothelial growth factor (VEGF); this leads, in turn, to increased tumour angiogenesis. Overexpression of miR-9 in otherwise non-metastatic breast tumour cells enables these cells to form pulmonary micrometastases in mice. Conversely, inhibiting miR-9 by using a 'miRNA sponge' in highly malignant cells inhibits metastasis formation. Expression of miR-9 is activated by MYC and MYCN, both of which directly bind to the mir-9-3 locus. Significantly, in human cancers, miR-9 levels correlate with MYCN amplification, tumour grade and metastatic status. These findings uncover a regulatory and signalling pathway involving a metastasis-promoting miRNA that is predicted to directly target expression of the key metastasis-suppressing protein E-cadherin
    Type of Publication: Journal article published
    PubMed ID: 20173740
    Signatur Availability
    BibTip Others were also interested in ...
  • 8
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; SITES ; GENE-EXPRESSION ; cell line ; DIFFERENTIATION ; NEUROBLASTOMA-CELLS ; CLEAVAGE ; AMPLIFICATION ; REGIONS ; DNA-DAMAGE ; REVEALS ; TUMOR-SUPPRESSOR ; senescence ; miRNA ; 3p25.3 ; p53 stabilization
    Abstract: Several microRNA (miRNA) loci are found within genomic regions frequently deleted in primary neuroblastoma, including miR-885-5p at 3p25.3. In this study, we demonstrate that miR-885-5p is downregulated on loss of 3p25.3 region in neuroblastoma. Experimentally enforced miR-885-5p expression in neuroblastoma cell lines inhibits proliferation triggering cell cycle arrest, senescence and/or apoptosis. miR-885-5p leads to the accumulation of p53 protein and activates the p53 pathway, resulting in upregulation of p53 targets. Enforced miR-885-5p expression consistently leads to downregulation of cyclin-dependent kinase (CDK2) and mini-chromosome maintenance protein (MCM5). Both genes are targeted by miR-885-5p via predicted binding sites within the 3'-untranslated regions (UTRs) of CDK2 and MCM5. Transcript profiling after miR-885-5p introduction in neuroblastoma cells reveals alterations in expression of multiple genes, including several p53 target genes and a number of factors involved in p53 pathway activity. Taken together, these data provide evidence that miR-885-5p has a tumor suppressive role in neuroblastoma interfering with cell cycle progression and cell survival.
    Type of Publication: Journal article published
    PubMed ID: 21233845
    Signatur Availability
    BibTip Others were also interested in ...
  • 9
    Keywords: EXPRESSION ; QUANTIFICATION ; GENE ; GENE-EXPRESSION ; GENOME ; SAMPLE ; transcription ; DIFFERENTIATION ; MOLECULES ; TISSUES ; MOLECULE ; PERFORMANCE ; PATTERNS ; gene expression ; genetics ; PCR ; PROBES ; neuroblastoma ; TIME QUANTITATIVE PCR ; ACCURATE ; MicroRNAs ; biotechnology ; MICRORNA ; gene expression analysis ; Genetic ; STRATEGY ; QUANTITATIVE PCR ; REFERENCE RNA
    Abstract: Gene expression analysis of microRNA molecules is becoming increasingly important. In this study we assess the use of the mean expression value of all expressed microRNAs in a given sample as a normalization factor for microRNA real-time quantitative PCR data and compare its performance to the currently adopted approach. We demonstrate that the mean expression value outperforms the current normalization strategy in terms of better reduction of technical variation and more accurate appreciation of biological changes
    Type of Publication: Journal article published
    PubMed ID: 19531210
    Signatur Availability
    BibTip Others were also interested in ...
  • 10
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; N-MYC ; TUMOR-SUPPRESSOR ; MICRORNA ; TRANSCRIPTIONAL TARGET ; THERAPEUTIC TARGET ; ACTIVATING MUTATIONS ; ALK KINASE
    Abstract: Neuroblastoma is an embryonic tumor arising from immature sympathetic nervous system cells. Recurrent genomic alterations include MYCN and ALK amplification as well as recurrent patterns of gains and losses of whole or large partial chromosome segments. A recent whole genome sequencing effort yielded no frequently recurring mutations in genes other than those affecting ALK. However, the study further stresses the importance of DNA copy number alterations in this disease, in particular for genes implicated in neuritogenesis. Here we provide additional evidence for the importance of focal DNA copy number gains and losses, which are predominantly observed in MYCN amplified tumors. A focal 5 kb gain encompassing the MYCN regulated miR-17 approximately 92 cluster as sole gene was detected in a neuroblastoma cell line and further analyses of the array CGH data set demonstrated enrichment for other MYCN target genes in focal gains and amplifications. Next we applied an integrated genomics analysis to prioritize MYCN down regulated genes mediated by MYCN driven miRNAs within regions of focal heterozygous or homozygous deletion. We identified RGS5, a negative regulator of G-protein signaling implicated in vascular normalization, invasion and metastasis, targeted by a focal homozygous deletion, as a new MYCN target gene, down regulated through MYCN activated miRNAs. In addition, we expand the miR-17 approximately 92 regulatory network controlling TGFss signaling in neuroblastoma with the ring finger protein 11 encoding gene RNF11, which was previously shown to be targeted by the miR-17 approximately 92 member miR-19b. Taken together, our data indicate that focal DNA copy number imbalances in neuroblastoma (1) target genes that are implicated in MYCN signaling, possibly selected to reinforce MYCN oncogene addiction and (2) serve as a resource for identifying new molecular targets for treatment.
    Type of Publication: Journal article published
    PubMed ID: 23308108
    Signatur Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...