miR-380-5p represses p53 to control cellular survival and is associated with poor outcome in MYCN-amplified neuroblastoma

Swarbrick, Alexander; Woods, Susan L.; Shaw, Alexander; Balakrishnan, Asha; Phua, Yuwei; Nguyen, Akira; Chanthery, Yvan H.; Lim, Lionel; Ashton, Lesley J.; Judson, Robert L.; Huskey, Noelle E.; Blelloch, Robert; Haber, Michelle; Norris, Murray D.; Lengyel, Péter; Hackett, Christopher S.; Preiß, Thomas; Chetcuti, Albert; Sullivan, Christopher S.; Marcusson, Eric G.; Weiss, William A.; L’Étoile, Noëlle D.; Goga, Andrei

doi:10.1038/nm.2227

Cited by 183 publications

(129 citation statements)

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“…The integration site locus contains a complex set of imprinted genes that are uniquely dysregulated after reprogramming to pluripotency (11), and two noncoding RNAs (Rian and Mirg) that contain multiple snoRNAs and microRNAs (12). These small RNAs could regulate a large number of target genes, and the human homologs of some of these microRNAs have been proposed to both stimulate and inhibit tumorigenesis in other types of malignancies (13)(14)(15)(16). Two recent studies found that a subset of human HCCs have elevated expression of this microRNA cluster (17,18).…”

mentioning

confidence: 99%

Induction of hepatocellular carcinoma by in vivo gene targeting

Wang¹,

Xu²,

Toffanin

et al. 2012

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

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The distinct phenotypic and prognostic subclasses of human hepatocellular carcinoma (HCC) are difficult to reproduce in animal experiments. Here we have used in vivo gene targeting to insert an enhancer-promoter element at an imprinted chromosome 12 locus in mice, thereby converting ∼1 in 20,000 normal hepatocytes into a focus of HCC with a single genetic modification. A 300-kb chromosomal domain containing multiple mRNAs, snoRNAs, and microRNAs was activated surrounding the integration site. An identical domain was activated at the syntenic locus in a specific molecular subclass of spontaneous human HCCs with a similar histological phenotype, which was associated with partial loss of DNA methylation. These findings demonstrate the accuracy of in vivo gene targeting in modeling human cancer and suggest future applications in studying various tumors in diverse animal species. In addition, similar insertion events produced by randomly integrating vectors could be a concern for liver-directed human gene therapy.

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mentioning

confidence: 99%

Induction of hepatocellular carcinoma by in vivo gene targeting

Wang¹,

Xu²,

Toffanin

et al. 2012

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

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“…Recent successful preclinical therapeutic trials in cancers include miR-380-5p replacement in neuroblastoma (26) and miR replacement/anti-miR combination therapy in hepatoblastoma (27). Notably, certain miR-based therapies have been applied in the clinic, including blockade of miR-122 for chronic viral hepatitis (28)(29).…”

Section: Discussionmentioning

confidence: 99%

miR-101 inhibits cell proliferation by targeting Rac1 in papillary thyroid carcinoma

Lin

Guan

et al. 2013

Biomedical Reports

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Abstract. Accumulating evidence suggests that some microRNAs (miRNAs) are involved in papillary thyroid carcinoma (PTC) progression. However, it remains necessary to elucidate the underlying molecular mechanisms involved. In the present study, we investigated the role of microRNA-101 (miR-101) in PTC via targeting of Ras-related C3 botulinum toxin substrate 1 (Rac1). The results showed that miR-101 was significantly downregulated in PTC tissues compared with adjacent normal tissues. Restoration of miR-101 expression significantly inhibited cell proliferation in the K1 PTC cell line. Moreover, algorithm-based and experimental strategies verified Rac1 as a direct target of miR-101 in the K1 cell line. Taken together, these findings suggest that miR-101 inhibited PTC growth via the downregulation of Rac1 expression, providing a better understanding of miRNA-modulated signaling networks for future cancer therapeutics.

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“…The Mdm2 +/− MYCN +/+ transgenics showed marked delay in tumour development and a lower overall tumour incidence compared to Mdm2 +/+ MYCN +/+ genotype, strongly implicating Mdm2-mediated blockade of p53 as an essential step in the pathogenesis of neuroblastoma. Recently, a miRNA (miR-380-5p), has been identified that represses p53 expression via a conserved sequence in the p53 3' untranslated region (Swarbrick, Woods et al, 2010). This miRNA is highly expressed in mouse embryonic stem cells and neuroblastomas, and its expression correlates with poor outcome in MYCN-amplified neuroblastoma.…”

Section: Targeting the P53 Pathwaymentioning

confidence: 99%