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Berlin Brandenburg

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  • 1
    In: Nature Medicine, 2010, Vol.16(10), p.1079
    Description: The tumor suppressor p53 is inactivated by genetic mutations in many cancers, except for neuroblastoma. New findings show that this cancer reversibly inhibits p53 through a microRNA, miR-380-5p. Blocking it to restore p53 function may be an attractive therapeutic option for neuroblastomas.
    Keywords: Cell Survival–Physiology ; Cell Transformation, Neoplastic–Pathology ; DNA Damage–Genetics ; Gene Amplification–Genetics ; Humans–Antagonists & Inhibitors ; Micrornas–Antagonists & Inhibitors ; Neuroblastoma–Antagonists & Inhibitors ; Nuclear Proteins–Antagonists & Inhibitors ; Oncogene Proteins–Antagonists & Inhibitors ; Tumor Suppressor Protein P53–Antagonists & Inhibitors ; Cancer ; Neurosciences ; Genetics ; Ribonucleic Acid–RNA ; Inhibitor Drugs ; Mycn Protein, Human ; Micrornas ; Nuclear Proteins ; Oncogene Proteins ; Tumor Suppressor Protein P53;
    ISSN: 1078-8956
    E-ISSN: 1546170X
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  • 2
    In: International Journal of Cancer, 15 August 2013, Vol.133(4), pp.908-919
    Description: High levels of the NTRK1/TrkA receptor are expressed in low‐stage neuroblastomas, which are characterized by a good patient prognosis and often undergo spontaneous regression. In addition to apoptosis, tumor‐immune responses might contribute to this regression. We hypothesized that TrkA expression might enhance the immune response to neuroblastomas. Immunohistochemistry on neuroblastoma tissue microarrays confirmed significantly higher lymphocyte infiltration in low‐stage compared with high‐stage tumors. Flow cytometry of human SH‐SY5Y cells stably transfected with cDNA revealed significant upregulation of major histocompatibility complex (MHC) class I complexes on TrkA‐expressing cells. Corresponding to this upregulation, T cell activity and cytoxicity was enhanced in the presence of SY5Y‐TrkA cells or by medium conditioned by them, suggesting the existence of additional soluble factors stimulating the T cell response. Activation of natural killer (NK) cells was only increased in the presence of SY5Y‐TrkA conditioned medium (CM) and not in co‐culture assays, suggesting a dominant inhibitory effect of upregulated MHC class I as the primary NK cell escape mechanism of TrkA‐expressing neuroblastomas. We reanalyzed gene expression data obtained from the cell culture model to identify additional genes involved in the TrkA‐mediated modulation of immune responses. Upregulation of selected target genes in SY5Y‐TrkA cells was confirmed on transcript and protein levels. However, none of the proteins were detected in medium conditioned by SY5Y‐TrkA cells, arguing against these factors as soluble mediators of the TrkA‐induced immune response. We here provide evidence that TrkA expression in neuroblastoma leads to an increased immunogenicity that may contribute to a less malignant phenotype and/or spontaneous regression of neuroblastoma cells. What's new? Elevated expression of neurotrophic tyrosine kinase type 1 receptor (NTRK1, or TrkA) previously was found to be associated with favorable prognosis in neuroblastoma. That effect may be the result of TrkA‐induced enhancement of the immune response toward neuroblastoma cells, as reported here. The findings suggest that TrkA‐associated immune activity might partly explain spontaneous regression of low‐stage neuroblastomas. They also have novel translational implications, among them the possibility for the development of T cell‐based immunotherapy approaches.
    Keywords: Neurotrophin Receptor ; Spontaneous Regression ; Cytotoxic Lymphocytes ; Nk Cells
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 3
    Language: English
    In: Cancer Research, 04/15/2013, Vol.73(8 Supplement), pp.4596-4596
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 4
    Language: English
    In: Cancer Research, 04/15/2012, Vol.72(8 Supplement), pp.1683-1683
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 5
    Language: English
    In: Progressive Neuroblastoma, 2015, Vol.20, p.35-46
    Description: Abstract MicroRNAs (miRNAs) are small noncoding RNAs that downregulate translation of mRNAs into proteins by specifically binding the 3′-untranslated regions (UTRs). miRNAs are deregulated in many cancer types, including neuroblastoma, and constitute a separate and potentially aberrant instance regulating protein expression. Once the pathogenic potential of miRNAs was recognized in tumor biology, miRNAs were suggested to contribute to MYCN signaling in neuroblastoma. Since then, miRNAs acting both upstream and downstream of MYCN have been identified. The MYCN 3′-UTR harbors binding sites for several miRNAs, including the let-7 family and miR-34a. Notably, these miRNAs can downregulate MYCN even in MYCN -amplified neuroblastoma cells. The most prominent miRNAs which act downstream of MYCN are the miRNAs of the miR-17-92 cluster and miR-9. These miRNAs are induced by MYCN, and act as oncogenes by downregulating tumor-suppressor genes. Here we review the pathogenic role of miRNAs acting upstream and downstream of MYCN in neuroblastoma tumor biology, and discuss how these miRNAs could be utilized as biomarkers, drug targets or even therapeutics. © 2015 S. Karger AG, Basel
    ISBN: 978-3-318-05496-5
    ISSN: 1017-5989
    E-ISSN: 1662-3886
    Source: Karger Book Series
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  • 6
    Language: English
    In: International Journal of Cancer, Sept 1, 2013, Vol.133(5), p.1064(10)
    Description: Byline: Kristina Althoff, Anneleen Beckers, Andrea Odersky, Pieter Mestdagh, Johannes Koster, Isabella M. Bray, Kenneth Bryan, Jo Vandesompele, Frank Speleman, Raymond L. Stallings, Alexander Schramm, Angelika Eggert, Angelika Eggert, Johannes H. Schulte Keywords: neuroblastoma; LSD1; miR-137; epigenetics Neuroblastoma is the most common extracranial solid tumor of childhood, and accounts for a1/415% of all childhood cancer deaths. The histone demethylase, lysine-specific demethylase 1 (KDM1A, previously known as LSD1), is strongly expressed in neuroblastomas, and overexpression correlates with poor patient prognosis. Inducing differentiation in neuroblastoma cells has previously been shown to down regulate KDM1A, and siRNA-mediated KDM1A knockdown inhibited neuroblastoma cell viability. The microRNA, miR-137, has been reported to be downregulated in several human cancers, and KDM1A mRNA was reported as a putative target of miR-137 in colon cancer. We hypothesized that miR-137 might have a tumor-suppressive role in neuroblastoma mediated via downregulation of KDM1A. Indeed, low levels of miR-137 expression in primary neuroblastomas correlated with poor patient prognosis. Re-expressing miR-137 in neuroblastoma cell lines increased apoptosis and decreased cell viability and proliferation. KDM1A mRNA was repressed by miR-137 in neuroblastoma cells, and was validated as a direct target of miR-137 using reporter assays in SHEP and HEK293 cells. Furthermore, siRNA-mediated KDM1A knockdown phenocopied the miR-137 re-expression phenotype in neuroblastoma cells. We conclude that miR-137 directly targets KDM1A mRNA in neuroblastoma cells, and activates cell properties consistent with tumor suppression. Therapeutic strategies to re-express miR-137 in neuroblastomas could be useful to reduce tumor aggressiveness. Author Affiliation: Article Note: A.S. and J.H.S. contributed equally to this work. Supporting information: Additional Supporting Information may be found in the online version of this article Additional Supporting Information may be found in the online version of this article.
    Keywords: Colon Cancer ; Tumors ; Microrna ; Neuroblastoma
    ISSN: 0020-7136
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  • 7
    Language: English
    In: 2012, Vol.7(8), p.e42025
    Description: Neuroblastoma is thought to originate from neural crest-derived cells. CD57 defines migratory neural crest cells in normal development and is expressed in neuroblastoma. ; We investigated the role of CD57 expression in neuroblastoma cells and . Compared to CD57 U-NB1 neuroblastoma cells, CD57 cells developed tumors with decreased latency after orthotopic transplantation into adrenal glands of mice. In addition, CD57 U-NB1 and SK-N-BE(2)-C neuroblastoma cells were also more clonogenic, induced more spheres and were less lineage-restricted. CD57 cells attached better to endothelial cells and showed enhanced invasiveness. While invasion of U-NB1 cells was inhibited by blocking antibodies against CD57, neither invasion of SK-N-BE(2)-C cells nor adhesion of U-NB1 and SK-N-BE(2)-C cells was attenuated. After tail vein injection only CD57 cells generated liver metastases, while overall metastatic rate was not increased as compared to CD57 cells. In stroma-poor neuroblastoma of patients CD57 cells were associated with undifferentiated tumor cells across all stages and tended to be more frequent after chemotherapy. ; Strong expression of CD57 correlates with aggressive attributes of U-NB1 and SK-N-BE(2)-C neuroblastoma cells and is linked with undifferentiated neuroblastoma cells in patients.
    Keywords: Research Article ; Biology ; Medicine ; Physiology ; Cell Biology ; Oncology ; Neuroscience ; Developmental Biology ; Pediatrics And Child Health
    E-ISSN: 1932-6203
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  • 8
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 09 July 2013, Vol.110(28), pp.E2592-601
    Description: Tumor cells activate autophagy in response to chemotherapy-induced DNA damage as a survival program to cope with metabolic stress. Here, we provide in vitro and in vivo evidence that histone deacetylase (HDAC)10 promotes autophagy-mediated survival in neuroblastoma cells. We show that both knockdown and inhibition of HDAC10 effectively disrupted autophagy associated with sensitization to cytotoxic drug treatment in a panel of highly malignant V-MYC myelocytomatosis viral-related oncogene, neuroblastoma derived-amplified neuroblastoma cell lines, in contrast to nontransformed cells. HDAC10 depletion in neuroblastoma cells interrupted autophagic flux and induced accumulation of autophagosomes, lysosomes, and a prominent substrate of the autophagic degradation pathway, p62/sequestosome 1. Enforced HDAC10 expression protected neuroblastoma cells against doxorubicin treatment through interaction with heat shock protein 70 family proteins, causing their deacetylation. Conversely, heat shock protein 70/heat shock cognate 70 was acetylated in HDAC10-depleted cells. HDAC10 expression levels in high-risk neuroblastomas correlated with autophagy in gene-set analysis and predicted treatment success in patients with advanced stage 4 neuroblastomas. Our results demonstrate that HDAC10 protects cancer cells from cytotoxic agents by mediating autophagy and identify this HDAC isozyme as a druggable regulator of advanced-stage tumor cell survival. Moreover, these results propose a promising way to considerably improve treatment response in the neuroblastoma patient subgroup with the poorest outcome.
    Keywords: Hdac Inhibitor ; Childhood Tumors ; Drug Resistance ; Autophagy -- Physiology ; Cell Survival -- Physiology ; Histone Deacetylases -- Physiology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 9
    Language: English
    In: PLoS ONE, 2011, Vol.6(9), p.e24584
    Description: Through negative regulation of gene expression, microRNAs (miRNAs) can function as oncosuppressors in cancers, and can themselves show altered expression in various tumor types. Here, we have investigated medulloblastoma tumors (MBs), which arise from an early impairment of developmental processes in the cerebellum, where Notch signaling is involved in many of the cell-fate-determining stages. Notch regulates a subset of MB cells that have stem-cell-like properties and can promote tumor growth. On the basis of this evidence, we hypothesized that miRNAs targeting the Notch pathway can regulate these phenomena, and can be used in anti-cancer therapies. ; In a screening of potential targets within Notch signaling, miR-34a was seen to be a regulator of the Notch pathway through its targeting of Notch ligand Delta-like 1 (Dll1). Down-regulation of Dll1 expression by miR-34a negatively regulates cell proliferation, and induces apoptosis and neural differentiation in MB cells. Using an inducible tetracycline on-off model of miR-34a expression, we show that in Daoy MB cells, Dll1 is the first target that is regulated in MB, as compared to the other targets analyzed here: Cyclin D1, cMyc and CDK4. MiR-34a expression negatively affects CD133/CD15 tumor-propagating cells, then we assay through reverse-phase proteomic arrays, Akt and Stat3 signaling hypo-phosphorylation. Adenoviruses carrying the precursor miR-34a induce neurogenesis of tumor spheres derived from a genetic animal model of MB (Patch1 p53), thus providing further evidence that the miR-34a/Dll1 axis controls both and signaling of Notch. , miR-34a overexpression carried by adenoviruses reduces tumor burden in cerebellum xenografts of athymic mice, thus demonstrating an anti-tumorigenic role of miR-34a . ; Despite advances in our understanding of the pathogenesis of MB, one-third of patients with MB remain incurable. Here, we show that stable nucleic-acid-lipid particles carrying mature miR-34a can target Dll1 and show equal effects to those of adenovirus miR-34a cell infection. Thus, this technology forms the basis for their therapeutic use for the delivery of miR-34a in brain-tumor treatment, with no signs of toxicity described to date in non-human primate trials.
    Keywords: Research Article ; Biology ; Materials Science ; Medicine ; Genetics And Genomics ; Biotechnology ; Oncology ; Pharmacology ; Pediatrics And Child Health
    E-ISSN: 1932-6203
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  • 10
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