Prediction of clinical outcome and biological characterization of neuroblastoma by expression profiling

Schramm, Alexander; Schulte, Johannes H.; Klein-Hitpaß, Ludger; Havers, W.; Sieverts, Hauke; Berwanger, Bernd; Christiansen, Holger; Warnat, Patrick; Brors, Benedikt; Eils, Jürgen; Eils, Roland; Eggert, Angelika

doi:10.1038/sj.onc.1208936

Cited by 106 publications

(63 citation statements)

References 36 publications

(35 reference statements)

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“…The latter is also associated with amplification of the MYCN oncogene, which is the strongest independent marker of outcome in NB (Nakagawara et al, 1994). On the other hand, the expressions of the neurotrophin receptors TrkA (Nakagawara et al, 1993) and TrkC (Yamashiro et al, 1997) are found in favorable NBs, with high expression of TrkA being accompanied by massive changes in the transcriptome of NBs (Schramm et al, 2005b). This biological diversity between TrkA and TrkB expression could also be verified in vitro (Lucarelli et al, 1997;Schramm et al, 2005a).…”

Section: Discussionmentioning

confidence: 89%

Galectin-1 is a major effector of TrkB-mediated neuroblastoma aggressiveness

et al. 2009

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Expression of Trk receptors is an important prognostic factor in neuroblastoma (NB) and other cancers. TrkB and its ligand brain-derived neurotrophic factor (BDNF) are preferentially expressed in NB with poor prognosis, conferring invasive and metastatic potential to the tumor cells as well as enhancing therapy resistance. Galectin-1 (Gal-1) has emerged as an interesting cancer target, as it is involved in modulating cell proliferation, cell death and cell migration, all of which are linked to cancer initiation and progression. We previously identified Gal-1 mRNA to be upregulated in patients with aggressive, relapsing NB and found that Gal-1 protein was upregulated in human SY5Y NB cells on activation of ectopically expressed TrkB (SY5Y-TrkB), but not TrkA (SY5Y-TrkA). Here, we report that Gal-1 mRNA levels positively correlated with TrkB expression and anticorrelated with TrkA expression in a cohort of 102 primary NB. Immunohistochemical analyses of 92 primary NB specimens revealed high Gal-1 expression in stromal septae and in neuroblasts. BDNF-mediated activation of TrkB enhanced invasiveness and migration in vitro, which could be impaired by transient transfection using Gal-1-specific siRNA or a neutralizing antibody directed against Gal-1. The addition of recombinant Gal-1 (rGal-1) in the absence of BDNF partially restored migration and invasive capacity. Using the Trk inhibitor K252a, we could show that the upregulation of Gal-1 protein strictly depended on activated TrkB. Our data suggest that targeting Gal-1 might be a promising strategy for the treatment of aggressive NB.

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Section: Discussionmentioning

confidence: 89%

Galectin-1 is a major effector of TrkB-mediated neuroblastoma aggressiveness

et al. 2009

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“…In published microarray expression analyses, high mRNA levels of the putative gene XM_496724 (corresponding to Nbla00301) have been found in superior cervical ganglion, adrenal gland, uterus, placenta, appendix, and liver. 6 Because SAGE, Northern blot, and semiquantitative RT-PCR suggested differential expression of DEIN variants A and B in different stages of neuroblastoma, its expression was evaluated in a cohort of 121 primary neuroblastoma specimens (stage I, n = 20; stage II, n = 8; stage III, n = 17; stage IV, n = 49; stage IVS, n = 27) by quantitative real-time RT-PCR with primers selectively detecting the major variants A and B as well as the minor variant E. A 140-fold oscillation between minimum and maximum relative mRNA levels with a median value of 22.4 was detected. Stage IVS tumors displayed a 3-fold higher median expression value for DEIN as compared with localized stage I to III or stage IV tumors (P < 0.001; Fig.…”

Section: Expression Of Dein In Normal Human Tissues and Neuroblastomamentioning

confidence: 99%

“…4D). Overall survival for these two groups was 0.93 F 0.03 and 0.78 6 GNF Expression Atlas 2 Data from U133A and GNF1H Chips: http:// genome.ucsc.edu/cgi-bin/hgGene. .…”

Section: Expression Of Dein In Normal Human Tissues and Neuroblastomamentioning

confidence: 99%

“…Whereas delayed onset of programmed cell death of neuroblasts has been proposed to account for the phenomenon of spontaneous regression of stage IVS disease and tumors in children diagnosed before the age of 1 year (2), the reasons for dissemination of disease before regression in stage IVS patients remain elusive. In recent years, gene expression profiling using microarrays has been used to identify the molecular characteristics of neuroblastoma (3)(4)(5)(6)(7)(8); however, whereas several gene expression patterns associated with favorable patients' outcome were described, none of these did contribute to the elucidation of the peculiar biology of stage IVS neuroblastoma or reported on a specific molecular marker defining this subtype of the disease.…”

Section: Introductionmentioning

confidence: 99%

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Identification of DEIN, a Novel Gene with High Expression Levels in Stage IVS Neuroblastoma

Voth

Oberthuer²,

Simon³

et al. 2007

Molecular Cancer Research

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Neuroblastoma at stage IVS, defined by dissemination to specific tissues and age <1 year at diagnosis, regularly follows spontaneous regression without cytotoxic treatment. To uncover the molecular characteristics of this subtype, Serial Analysis of Gene Expression (SAGE) profiles from stage IVS and fatal stage IV tumors were compared. A SAGE tag (GCAACTTAAC) was detected that was overrepresented in stage IVS disease and that had no reliable match in current National Center for Biotechnology Information databases of SAGE profiles, thus pointing to a novel gene. The corresponding gene, which maps to chromosome 4q33-34, was identified using a modified 3 ¶-and 5 ¶-rapid amplification of cDNA ends PCR and was designated as DEIN (differentially expressed in neuroblastoma). The gene comprises five transcript variants and its sequence overlaps with expressed sequences of the yet uncharacterized UniGene cluster Hs.61435. DEIN exhibits nucleotide sequence conservation over a broad range of species with an overall homology of 65% between human and mouse. As none of the predicted amino acid sequences is homologous to known proteins, it remains to be determined whether DEIN represents a coding or noncoding RNA. Northern blot analysis and semiquantitative reverse transcription-PCR showed high DEIN expression in neuroblastoma, whereas expression was absent or weak in most normal adult tissues. Analysis of 121 primary neuroblastomas by real-time reverse transcription-PCR revealed a strong association with age at diagnosis <1 year and particularly with stage IVS disease (both P < 0.001). The characteristic expression pattern of DEIN suggests a specific role of this gene in the unique biology of stage IVS tumors and may help to molecularly define this special subtype of neuroblastoma. (Mol Cancer Res 2007;5(12):1276 -84)

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“…4 Using high throughput gene expression profiling, distinct sets of MYCN-regulated target genes have been identified in neuroblastoma. [5][6][7][8][9] In addition to numerous genes induced by MYCN, all studies have reported significant numbers of genes to be downregulated. MYCN induces gene transcription via the specific E-box sequences in target gene promoters.…”

mentioning

confidence: 99%

MYCN regulates oncogenic MicroRNAs in neuroblastoma

Schulte

Horn

Otto

et al. 2007

Intl Journal of Cancer

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242

188

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MYCN amplification is a common feature of aggressive tumour biology in neuroblastoma. The MYCN transcription factor has been demonstrated to induce or repress expression of numerous genes. MicroRNAs (miRNA) are a recently discovered class of short RNAs that repress translation and promote mRNA degradation by sequence-specific interaction with mRNA. Here, we sought to analyse the role of MYCN in regulation of miRNA expression. Using a miRNA microarray containing 384 different miRNAs and a set of 160 miRNA real-time PCR assays to validate the microarray results, 7 miRNAs were identified that are induced by MYCN in vitro and are upregulated in primary neuroblastomas with MYCN amplification. Three of the seven miRNAs belong to the miR-106a and miR-17 clusters, which have previously been shown to be regulated by c-Myc. The miR-17-92 polycistron also acts as an oncogene in haematopoietic progenitor cells. We show here that miR-221 is also induced by MYCN in neuroblastoma. Previous studies have reported miR-221 to be overexpressed in several other cancer entities, but its regulation has never before been associated with Myc. We present evidence of miRNA dysregulation in neuroblastoma. Additionally, we report miRNA induction to be a new mechanism of gene expression downregulation by MYCN. ' 2007 Wiley-Liss, Inc.

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Prediction of clinical outcome and biological characterization of neuroblastoma by expression profiling

Cited by 106 publications

References 36 publications

Galectin-1 is a major effector of TrkB-mediated neuroblastoma aggressiveness

Galectin-1 is a major effector of TrkB-mediated neuroblastoma aggressiveness

Identification of DEIN, a Novel Gene with High Expression Levels in Stage IVS Neuroblastoma

MYCN regulates oncogenic MicroRNAs in neuroblastoma

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