Distinct transcriptional MYCN/c-MYC activities are associated with spontaneous regression or malignant progression in neuroblastomas

Westermann, Frank; Muth, Daniel; Benner, Axel; Bauer, Tobias; Henrich, Kai Oliver; Oberthuer, André; Brors, Benedikt; Beißbarth, Tim; Vandesompele, Jo; Pattyn, Filip; Hero, Barbara; König, Rainer; Fischer, Matthias; Schwab, Manfred

doi:10.1186/gb-2008-9-10-r150

Cited by 231 publications

(270 citation statements)

References 47 publications

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“…This additional separation suggests that MYCN/c-MYC signaling rather than MYCN levels alone underlies the differential expression of this miRNA signature. Indeed, c-MYC expression is Figure S2), confirming the inverse relationship between MYCN and c-MYC (Vandesompele et al, 2003), and has been shown to drive MYCN/c-MYC mRNA target gene expression in these tumors (Westermann et al, 2008). In addition, other genetic factors than increased MYCN/c-MYC activity could also contribute to the observed miRNA expression differences.…”

Section: Mycn/c-myc Microrna Signature Delineationsupporting

confidence: 61%

“…Patients in the first quartile, representing tumors with the lowest expression of predicted 8mer miRNA targets, have a particular poor prognosis as compared with those in the fourth quartile. Of interest, 48% of the tumors in the first quartile (n ¼ 66) were MYCN single-copy confirming that MYCN/c-MYC signaling rather than MYCN amplification underlies the poor outcome of these patients (Fredlund et al, 2008;Westermann et al, 2008). Moreover, 8mer miRNA-mediated target repression but not MYCN amplification status was an independent factor in a multivariate Cox regression model for EFS and OS (Supplementary Table S3).…”

Section: Mycn/c-myc-activated Micrornas Act In Concertmentioning

confidence: 83%

“…Chromatin immunoprecipitation was performed as described earlier using 10 mg of MYCN or c-MYC antibodies (Westermann et al, 2008). For a detailed description see Supplementary Material.…”

Section: Chromatin Immunoprecipitationmentioning

confidence: 99%

“…Activated MYCN/c-MYC signaling is a hallmark of poor prognosis for neuroblastoma tumors (Fredlund et al, 2008) and can be caused either by MYCN amplification (Seeger et al, 1985) or increased c-MYC expression in stage 4 MYCN non-amplified neuroblastoma tumors (Westermann et al, 2008). This increase in MYCN/c-MYC expression results in the activation of coding target genes related to poor patient prognosis independently of MYCN amplification (Fredlund et al, 2008;Westermann et al, 2008).…”

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: Mycn/c-myc Microrna Signature Delineationsupporting

confidence: 61%

Section: Mycn/c-myc-activated Micrornas Act In Concertmentioning

confidence: 83%

“…Chromatin immunoprecipitation was performed as described earlier using 10 mg of MYCN or c-MYC antibodies (Westermann et al, 2008). For a detailed description see Supplementary Material.…”

Section: Chromatin Immunoprecipitationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…Based on the observation that stage 4S NB with higher levels of N-Myc proteins are more prone to spontaneous regression by apoptosis [35] or neuronal differentiation [36], it has been speculated that MYCN not only mediates malignant progression, but is also involved in spontaneous regression in favorable NB [37]. We, and others, have demonstrated that inhibition of MYCN leads to MYC upregulation [38]. For all these reasons, both MYC family members have to be simultaneously targeted.…”

Section: Twist1 Targeted Therapymentioning

confidence: 99%

Considerations for the Development of Innovative Therapies Against Aggressive Neuroblastoma: Immunotherapy and Twist1 Targeting

Shekarian¹,

Valsesia‐Wittmann²

2017

Neuroblastoma - Current State and Recent Updates

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Neuroblastoma (NB) is one of the major challenges of pediatric oncology with a 5-year survival rate of less than 40% despite intense therapy. The aggressiveness of the disease has been recently correlated to the degree of myeloid cells infiltrating the tumor. Together with the tumor cells and immunosuppressive cytokines (e.g., IL-10 and TGF-β), these cells hamper the generation of an efficient antitumor immune response and, therefore, favor tumor growth and metastasis. Novel therapeutic approaches are designed to target immune cells instead of cancer cells. To improve their efficacy, recent cancer immunotherapy strategies have focused on the depletion, blockade, or reprogramming of these tolerogenic immune effectors. Therefore, the principal clinical challenge is currently to identify therapeutic strategies which could overcome the primary and secondary resistances to these cancer immunotherapies. In this review, we discuss the dialogue of immune microenvironment of neuroblastoma and the immunotherapeutic strategies to cure neuroblastoma.

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miR‐15a‐5p, miR‐15b‐5p, and miR‐16‐5p inhibit tumor progression by directly targeting MYCN in neuroblastoma

et al. 2019

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Neuroblastoma (NB) is the most common extracranial solid malignancy in children. Despite current aggressive treatment regimens, the prognosis for high‐risk NB patients remains poor, with the survival of less than 40%. Amplification/stabilization of MYCN oncogene, in NB is associated with a high risk of recurrence. Thus, there is an urgent need for novel therapeutics. The deregulated expression of microRNA (miR) is reported in NB; nonetheless, its effect on MYCN regulation is poorly understood. First, we identified that miR‐15a‐5p, miR‐15b‐5p, and miR‐16‐5p (hereafter miR‐15a, miR‐15b or miR‐16) were down‐regulated in patient‐derived xenografts (PDX) with high MYCN expression. MiR targeting sequences on MYCN mRNA were predicted using online databases such as TargetScan and miR database. The R2 database, containing 105 NB patients, showed an inverse correlation between MYCN mRNA and deleted in lymphocytic leukemia (DLEU) 2, a host gene of miR‐15. Moreover, overexpression of miR‐15a, miR‐15b or miR‐16 significantly reduced the levels of MYCN mRNA and N‐Myc protein. Conversely, inhibiting miR dramatically enhanced MYCN mRNA and N‐Myc protein levels, as well as increasing mRNA half‐life in NB cells. By performing immunoprecipitation assays of argonaute‐2 (Ago2), a core component of the RNA‐induced silencing complex, we showed that miR‐15a, miR‐15b and miR‐16 interact with MYCN mRNA. Luciferase reporter assays showed that miR‐15a, miR‐15b and miR‐16 bind with 3’UTR of MYCN mRNA, resulting in MYCN suppression. Moreover, induced expression of miR‐15a, miR‐15b and miR‐16 significantly reduced the proliferation, migration, and invasion of NB cells. Finally, transplanting miR‐15a‐, miR‐15b‐ and miR‐16‐expressing NB cells into NSG mice repressed tumor formation and MYCN expression. These data suggest that miR‐15a, miR‐15b and miR‐16 exert a tumor‐suppressive function in NB by targeting MYCN. Therefore, these miRs could be considered as potential targets for NB treatment.

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Distinct transcriptional MYCN/c-MYC activities are associated with spontaneous regression or malignant progression in neuroblastomas

Cited by 231 publications

References 47 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

Considerations for the Development of Innovative Therapies Against Aggressive Neuroblastoma: Immunotherapy and Twist1 Targeting

miR‐15a‐5p, miR‐15b‐5p, and miR‐16‐5p inhibit tumor progression by directly targeting MYCN in neuroblastoma

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