miR-380-5p represses p53 to control cellular survival and is associated with poor outcome in MYCN-amplified neuroblastoma
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.
|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.;|
|Responsible Garvan Author|
|Publisher Name||NATURE MEDICINE|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20871609|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/10791|