MYCN regulates oncogenic MicroRNAs in neuroblastoma

Schulte, Johannes H.; Horn, Sebastian; Otto, Tobias; Samans, Birgit; Heukamp, Lukas C.; Eilers, Ursula-Christa; Krause, Michael; Astrahantseff, Kathy; Klein-Hitpaß, Ludger; Buettner, Reinhard; Schramm, Alexander; Christiansen, Holger; Eilers, Martin; Eggert, Angelika; Berwanger, Bernd

doi:10.1002/ijc.23153

Cited by 242 publications

(213 citation statements)

References 38 publications

(43 reference statements)

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“…The functional overlap between MYCN and c-MYC is further substantiated by the identification of a c-MYC-translocated neuroblastoma tumor with a mRNA, miRNA and genomic profile that is typical for a MYCN-amplified tumor. It is also perfectly in line with previous reports on miRNAs commonly regulated by c-MYC and MYCN (Chen and Stallings, 2007;Chang et al, 2008;Sander et al, 2008;Schulte et and with the observation that MYCN can functionally replace c-MYC in murine development (Malynn et al, 2000). Whether c-MYC is capable of replacing MYCN remains to be determined but could further corroborate these findings.…”

Section: Discussionsupporting

confidence: 91%

“…These small non-coding RNAs have an effect on virtually every aspect of tumorigenesis and function as negative regulators of messenger RNA (mRNA) levels and translation (Bartel, 2009). Some miRNAs, such as those belonging to the oncogenic miR-17-92 cluster, have been shown to be important players in MYCN/c-MYC signaling (O'Donnell et al, 2005;Dews et al, 2006;Chang et al, 2008;Fontana et al, 2008;Schulte et al, 2008;Northcott et al, 2009). However, a more general insight in the relationship between miRNAs and mRNAs within the MYCN/c-MYC transcriptional network remains to be examined.…”

Section: Introductionmentioning

confidence: 99%

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MYCN/c-MYC-induced microRNAs repress coding gene networks associated with poor outcome in MYCN/c-MYC-activated tumors

et al. 2009

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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-MYCand 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.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

MYCN/c-MYC-induced microRNAs repress coding gene networks associated with poor outcome in MYCN/c-MYC-activated tumors

et al. 2009

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“…In doxycycline (Dox)-free medium, Tet21N cells express exogenous MYCN in levels similar to common NB cell lines (16). We observed consistent upregulation of several MYC-associated miRNAs previously identified (17,18), including miRNAs from the oncogenic miR-17∼92 cluster (e.g., miR-17, miR-18a, and miR-19a) (19) and its paralogs on chromosome 7 and chromosome X (Fig. 1A, Fig.…”

Section: Expression Analysis Of Mirnas In Tet21n Cells Reveals Specifsupporting

confidence: 82%

MYCN-regulated microRNAs repress estrogen receptor-α ( ESR1 ) expression and neuronal differentiation in human neuroblastoma

Lovén

Zinin

Wahlström

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

124

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MYCN, a proto-oncogene normally expressed in the migrating neural crest, is in its amplified state a key factor in the genesis of human neuroblastoma (NB). However, the mechanisms underlying MYCN-mediated NB progression are poorly understood. Here, we present a MYCN-induced miRNA signature in human NB involving the activation and transrepression of several miRNA genes from paralogous clusters. Several family members derived from the miR-17∼92 cluster, including miR-18a and miR-19a, were among the up-regulated miRNAs. Expression analysis of these miRNAs in NB tumors confirmed increased levels in MYCN-amplified samples. Specifically, we show that miR-18a and miR-19a target and repress the expression of estrogen receptor-α (ESR1), a ligand-inducible transcription factor implicated in neuronal differentiation. Immunohistochemical staining demonstrated ESR1 expression in human fetal sympathetic ganglia, suggesting a role for ESR1 during sympathetic nervous system development. Concordantly, lentiviral restoration of ESR1 in NB cells resulted in growth arrest and neuronal differentiation. Moreover, lentiviral-mediated inhibition of miR-18a in NB cells led to severe growth retardation, outgrowth of varicosity-containing neurites, and induction of neuronal sympathetic differentiation markers. Bioinformatic analyses of microarray data from NB tumors revealed that high ESR1 expression correlates with increased event-free survival in NB patients and favorable disease outcome. Thus, MYCN amplification may disrupt estrogen signaling sensitivity in primitive sympathetic cells through deregulation of ESR1, thereby preventing the normal induction of neuroblast differentiation. Collectively, our findings demonstrate the molecular consequences of abnormal miRNA transcription in a MYCN-driven tumor and offer unique insights into the pathology underlying MYCN-amplified NB.oncogene | embryonic development | pediatric tumor | transcription factor | hormone receptor N euroblastoma (NB) represents a remarkably heterogeneous pediatric cancer derived from precursor cells of the sympathetic ganglionic lineage, with clinical behavior ranging from spontaneous regression to rapid progression and death (1, 2). Despite the frequent display of multiple genetic defects, including chromosomal gains and losses, aneuploidy, and amplification of chromosomal material, few established molecular genetic markers associate with disease outcome. Amplification of the MYCN locus, present in ≈20 to 30% of all cases, represents the most important genetic aberration, and is strongly related to poor clinical diagnosis (3). MYCN is expressed in the migrating neural crest and encodes a phosphoprotein that belongs to the Myc network of helix-loop-helix leucine zipper transcriptional regulators, which play key roles in governing cell growth, apoptosis, and differentiation (4). Transcriptional activation is mediated by binding of the Myc/Max dimer to the consensus E-box sequence CA(C/T)GTG in target gene promoters while the mechanism of Myc-mediated transcriptional r...

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“…Others have confirmed that miR-17/92 is regulated by N-myc, a direct target of SHH in CGNPs. 45 To further explore the relationship between SHH signaling, proliferation and miR-17/92, we treated mouse CGNPs with SHH or vehicle and profiled the cell lysates by miRNA microarray. These experiments confirmed miR-17/92 as a target of SHH signaling in CGNPs, an effect we determined to be mediated through N-Myc.…”

Section: Discussionmentioning

confidence: 99%

Normal and oncogenic roles for microRNAs in the developing brain

Fernández-L¹,

Northcott²,

Taylor³

et al. 2009

Cell Cycle

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M icroRNAS (miRNAs) are smallendogenous non-coding RNAs that play important roles in many different biological processes including proliferation, differentiation and apoptosis through silencing of target genes. Emerging evidence indicates that miRNAs are key players in mammalian development that, when altered, contribute to tumorigenesis. However, only a few studies to date have focused on the role of miRNAs in medulloblastoma, the most common malignant pediatric brain tumor. These tumors arise in the cerebellum and may attribute their origins to deregulated proliferation of neural progenitor cells during development. Understanding the interplay between normal brain development and medulloblastoma pathogenesis is necessary in order for more efficient, less toxic targeted therapies to be developed and implemented. MiRNA expression profiling of both mouse and human medulloblastomas has led to the identification of signatures correlating with the molecular subgroups of medulloblastoma, tumor diagnosis and response to treatment, as well as novel targets of potential clinical relevance. This review summarizes the recent miRNA literature in both medulloblastoma and normal brain development.

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MYCN regulates oncogenic MicroRNAs in neuroblastoma

Cited by 242 publications

References 38 publications

MYCN/c-MYC-induced microRNAs repress coding gene networks associated with poor outcome in MYCN/c-MYC-activated tumors

MYCN/c-MYC-induced microRNAs repress coding gene networks associated with poor outcome in MYCN/c-MYC-activated tumors

MYCN-regulated microRNAs repress estrogen receptor-α ( ESR1 ) expression and neuronal differentiation in human neuroblastoma

Normal and oncogenic roles for microRNAs in the developing brain

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