Swarbrick A, Woods SL, Shaw A, Balakrishnan A, Phua Y, Nguyen A et al.. miR-380-5p represses p53 to control cellular survival and is associated with poor outcome in MYCN-amplified neuroblastoma. Nat Med 16: 1134-1140

Cancer Research Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Nature medicine (Impact Factor: 27.36). 10/2010; 16(10):1134-40. DOI: 10.1038/nm.2227
Source: PubMed


Inactivation of the p53 tumor suppressor pathway allows cell survival in times of stress and occurs in many human cancers; however, normal embryonic stem cells and some cancers such as neuroblastoma maintain wild-type human TP53 and mouse Trp53 (referred to collectively as p53 herein). Here we describe a miRNA, miR-380-5p, that represses p53 expression via a conserved sequence in the p53 3' untranslated region (UTR). miR-380-5p is highly expressed in mouse embryonic stem cells and neuroblastomas, and high expression correlates with poor outcome in neuroblastomas with neuroblastoma derived v-myc myelocytomatosis viral-related oncogene (MYCN) amplification. miR-380 overexpression cooperates with activated HRAS oncoprotein to transform primary cells, block oncogene-induced senescence and form tumors in mice. Conversely, inhibition of endogenous miR-380-5p in embryonic stem or neuroblastoma cells results in induction of p53, and extensive apoptotic cell death. In vivo delivery of a miR-380-5p antagonist decreases tumor size in an orthotopic mouse model of neuroblastoma. We demonstrate a new mechanism of p53 regulation in cancer and stem cells and uncover a potential therapeutic target for neuroblastoma.

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    • "This does not preclude that other miRNAs may be involved. Furthermore, p53 translation is also known to be regulated by the binding of various proteins to its mRNA that may be investigated in future studies (Herrera-Merchan et al., 2010; Hu et al., 2010; Swarbrick et al., 2010; Tian et al., 2010; Vilborg et al., 2010). "
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    • "The tumor suppressor p53 is very rarely mutated in primary neuroblastoma at diagnosis and its downstream effectors are functionally intact [8], [54]. However, multiple hits seem to cooperate to impair p53 functions in neuroblastoma, including deregulation of the ARF/MDM2 pathway [55], expression of microRNAs targeting p53 pathways [56], and repression of p53-mediated autophagy [57]. We demonstrate here that transcriptional profiles of high-risk neuroblastoma show over- expression of genes that are repressed by p53, and furthermore, a subset of these genes has strong prognostic value, suggesting they are involved in overcoming chemotherapy-induced p53 activity. "
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    ABSTRACT: Chemotherapy induces apoptosis and tumor regression primarily through activation of p53-mediated transcription. Neuroblastoma is a p53 wild type malignancy at diagnosis and repression of p53 signaling plays an important role in its pathogenesis. Recently developed small molecule inhibitors of the MDM2-p53 interaction are able to overcome this repression and potently activate p53 dependent apoptosis in malignancies with intact p53 downstream signaling. We used the small molecule MDM2 inhibitor, Nutlin-3a, to determine the p53 drug response signature in neuroblastoma cells. In addition to p53 mediated apoptotic signatures, GSEA and pathway analysis identified a set of p53-repressed genes that were reciprocally over-expressed in neuroblastoma patients with the worst overall outcome in multiple clinical cohorts. Multifactorial regression analysis identified a subset of four genes (CHAF1A, RRM2, MCM3, and MCM6) whose expression together strongly predicted overall and event-free survival (p<0.0001). The expression of these four genes was then validated by quantitative PCR in a large independent clinical cohort. Our findings further support the concept that oncogene-driven transcriptional networks opposing p53 activation are essential for the aggressive behavior and poor response to therapy of high-risk neuroblastoma.
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    • "Such studies have shown that administration of chemical mimics of tumor suppressive miR, or chemical antagonists of pro-tumorigenic miRs, can have potent effects on tumor growth or/and dissemination in disease animal models. Examples of successful preclinical therapeutic trials in pediatric cancers include miR-380-5p replacement in neuroblastoma (Swarbrick et al., 2010), and miR replacement/anti-miR combination therapy, involving miR-100 and miR-371 clusters, in hepatoblastoma (Cairo et al., 2010). Thus, miR manipulation in vivo can affect disease phenotypes. "
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