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

Abstract

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.

Type Journal
ISBN 1546-170X (Electronic) 1078-8956 (Linking)
Authors Swarbrick, A.; Woods, S. L.; Shaw, A.; Balakrishnan, A.; Phua, Y.; Nguyen, A.; Chanthery, Y.; Lim, L.; Ashton, L. J.; Judson, R. L.; Huskey, N.; Blelloch, R.; Haber, M.; Norris, M. D.; Lengyel, P.; Hackett, C. S.; Preiss, T.; Chetcuti, A.; Sullivan, C. S.; Marcusson, E. G.; Weiss, W.; L'Etoile, N.; Goga, A.;
Garvan Authors Dr Akira Nguyen , Dr Alex Swarbrick
Publisher Name NAT MED
Published Date 2010-01-01 00:00:00
Published Volume 16
Published Issue 10
Published Pages 1134-40
URL http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20871609
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?10791_11166/10 Swarbrick NM_.pdf