Network Modeling of microRNA–mRNA Interactions in Neuroblastoma Tumorigenesis Identifies miR-204 as a Direct Inhibitor of MYCN

Ooi, Chi Yan; Carter, Daniel; Liu, Bing; Mayoh, Chelsea; Beckers, Anneleen; Lalwani, Amit; Nagy, Zsuzsanna; Brouwer, Sara De; Decaesteker, Bieke; Hung, Tzong-Tyng; Norris, Murray D.; Haber, Michelle; Liu, Tao; Preter, Katleen De; Speleman, Franki; Cheung, Belamy B.; Marshall, Glenn M.

doi:10.1158/0008-5472.can-17-3034

Cited by 51 publications

(39 citation statements)

References 54 publications

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“…Previous investigations have found the interconnection between MYCN and miRNAs. For example, a study based on the modeling of miRNA‐mRNA interactions identified a regulatory network involving MYCN and the tumor suppressor miR‐204 that operated during neuroblastoma tumorigenesis . This work showed that miR‐204 directly bound MYCN mRNA and decreased its protein levels.…”

Section: Discussionmentioning

confidence: 99%

“…For example, a study based on the modeling of miRNA-mRNA interactions identified a regulatory network involving MYCN and the tumor suppressor miR-204 that operated during neuroblastoma tumorigenesis. 42 This work showed that miR-204 directly bound MYCN mRNA and decreased its protein levels. Additionally, MYCN was able to bind the promoter of miR-204 and inhibit the expression F I G U R E 7 Assessment of microRNA (miR)-493-5p tumor suppressor activity by gene set enrichment analysis (GSEA).…”

Section: Hep3b Hep3b Hepg2mentioning

confidence: 91%

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MicroRNA‐493‐5p‐mediated repression of the MYCN oncogene inhibits hepatic cancer cell growth and invasion

Yasukawa

Liew

Hagiwara³

et al. 2020

Cancer Science

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Primary hepatic tumors mainly include hepatocellular carcinoma (HCC), which is one of the most frequent causes of cancer‐related deaths worldwide. Thus far, HCC prognosis has remained extremely poor given the lack of effective treatments. Numerous studies have described the roles played by microRNAs (miRNAs) in cancer progression and the potential of these small noncoding RNAs for diagnostic or therapeutic applications. The current consensus supports the idea that direct repression of a wide range of oncogenes by a single key miRNA could critically affect the malignant properties of cancer cells in a synergistic manner. In this study, we aimed to investigate the oncogenes controlled by miR‐493‐5p, a major tumor suppressor miRNA that inactivates miR‐483‐3p oncomir in hepatic cancer cells. Using global gene expression analysis, we highlighted a set of candidate genes potentially regulated by miR‐493‐5p. In particular, the canonical MYCN protooncogene (MYCN) appeared to be an attractive target of miR‐493‐5p given its significant inhibition through 3′‐UTR targeting in miR‐493‐5p‐rescued HCC cells. We showed that MYCN was overexpressed in liver cancer cell lines and clinical samples from HCC patients. Notably, MYCN expression levels were inversely correlated with miR‐493‐5p in tumor tissues. We confirmed that MYCN knockdown mimicked the anticancer effect of miR‐493‐5p by inhibiting HCC cell growth and invasion, whereas MYCN rescue hindered miR‐493‐5p activity. In summary, miR‐493‐5p is a pivotal miRNA that modulates various oncogenes after its reexpression in liver cancer cells, suggesting that tumor suppressor miRNAs with a large spectrum of action could provide valuable tools for miRNA replacement therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Hep3b Hep3b Hepg2mentioning

confidence: 91%

MicroRNA‐493‐5p‐mediated repression of the MYCN oncogene inhibits hepatic cancer cell growth and invasion

Yasukawa

Liew

Hagiwara³

et al. 2020

Cancer Science

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“…PHOX2B overexpression in NB may be ascribed to different causes, among which the lack of miR‐204‐mediated down‐regulation of its mRNA, due to reduced miR‐204 expression in NB samples . miR‐204 has recently revealed to be a key microRNA in NB development as, in addition to PHOX2B , also MYCN has been identified among its target genes, thus suggesting an interplay among PHOX2B , miR‐204, and MYCN in this tumor. Moreover, PHOX2B expression in NB cell lines correlates with presence of specific 3′UTR haplotypes.…”

Section: Phox2b Gene Variantsmentioning

confidence: 99%

“…[71][72][73] PHOX2B overexpression in NB may be ascribed to different causes, among which the lack of miR-204-mediated down-regulation of its mRNA, due to reduced miR-204 expression in NB samples. 25,74 miR-204 has recently revealed to be a key microRNA in NB development as, in addition to PHOX2B, also MYCN has been identified among its target genes, 75 thus suggesting an interplay among PHOX2B, Figure 2) are found in PHOX2B-related diseases with a certain frequency. This observation prompts to further investigate larger cohorts to demonstrate a possible causative or predisposing implication for these seemingly benign variants.…”

Section: Role Of Phox2b Gene Expression and Common Phox2b Variantsmentioning

confidence: 99%

Causative and common PHOX2B variants define a broad phenotypic spectrum

Bachetti

Ceccherini

2019

Clinical Genetics

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“…Another class of regulators of MYCN expression is microRNAs (miRNAs). Multiple miRNAs have been identified to regulate MYCN expression either by directly targeting the 3′ untranslated region (3'UTR) of MYCN mRNA or through indirect pathways [17][18][19]. Our group previously identified miR-506-3p as a potent differentiation inducer and a strong repressor of MYCN expression in neuroblastoma cells [17,20].…”

Section: Introductionmentioning

confidence: 99%

The PLAGL2/MYCN/miR-506-3p interplay regulates neuroblastoma cell fate and associates with neuroblastoma progression

Zhao

Shelton

Oviedo

et al. 2020

J Exp Clin Cancer Res

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Background: The oncogene MYCN is critical for tumorigenesis of several types of cancers including neuroblastoma. We previously reported that miR-506-3p repressed MYCN expression in neuroblastoma cells. However, the mechanism underlying such regulation was undetermined since there is no miR-506-3p target site in MYCN 3'UTR. Methods: By a systematic investigation combining microarray, informatics and luciferase reporter assay, we identified that the transcriptional factor pleiomorphic adenoma gene-like 2 (PLAGL2) is a direct target of miR-506-3p that mediates its regulation on MYCN expression. Using CHIP-PCR and luciferase reporter assay, we validated the transcriptional regulation of MYCN by PLAGL2 and we further demonstrated the transcriptional regulation of PLAGL2 by MYCN. We examined the function of PLAGL2 in regulating neuroblastoma cell fate by cell viability assay, colony formation and Western blotting of differentiation markers. We examined the effect of retinoic acid, the differentiation agent used in neuroblastoma therapy, on miR-506-3p, PLAGL2 and MYCN expressions by quantitative PCR and Western blots. We investigated the clinical relevance of PLAGL2 expression by examining the correlation of tumor PLAGL2 mRNA levels with MYCN mRNA expression and patient survival using public neuroblastoma patient datasets. Results: We found that miR-506-3p directly down-regulated PLAGL2 expression, and we validated a PLAGL2 binding site in the MYCN promoter region responsible for promoting MYCN transcription, thereby establishing a mechanism through which miR-506-3p regulates MYCN expression. Conversely, we discovered that MYCN regulated PLAGL2 transcription through five N-Myc-binding E-boxes in the PLAGL2 promoter region. We further confirmed the reciprocal regulation between endogenous PLAGL2 and MYCN in multiple neuroblastoma cell lines. Moreover, we found that PLAGL2 knockdown induced neuroblastoma cell differentiation and reduced cell proliferation, and combined knockdown of PLAGL2 and MYCN showed a synergistic effect. More strikingly, we found that high tumor PLAGL2 mRNA levels were significantly correlated with high MYCN mRNA levels and poor patient survival in neuroblastoma patients. Furthermore, we found that retinoic acid increased expression of miR-506-3p and repressed expression of MYCN and PLAGL2. Conclusions: Our findings altogether suggest that the interplay network formed by PLAGL2, MYCN and miR-506-3p is an important mechanism in regulating neuroblastoma cell fate, determining neuroblastoma prognosis, and mediating the therapeutic function of retinoic acid.

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Network Modeling of microRNA–mRNA Interactions in Neuroblastoma Tumorigenesis Identifies miR-204 as a Direct Inhibitor of MYCN

Cited by 51 publications

References 54 publications

MicroRNA‐493‐5p‐mediated repression of the MYCN oncogene inhibits hepatic cancer cell growth and invasion

MicroRNA‐493‐5p‐mediated repression of the MYCN oncogene inhibits hepatic cancer cell growth and invasion

Causative and common PHOX2B variants define a broad phenotypic spectrum

The PLAGL2/MYCN/miR-506-3p interplay regulates neuroblastoma cell fate and associates with neuroblastoma progression

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