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.
Swarbrick
Alexander
A
Cancer Research Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. a.swarbrick@garvan.org.au
Woods
Susan L
SL
Shaw
Alexander
A
Balakrishnan
Asha
A
Phua
Yuwei
Y
Nguyen
Akira
A
Chanthery
Yvan
Y
Lim
Lionel
L
Ashton
Lesley J
LJ
Judson
Robert L
RL
Huskey
Noelle
N
Blelloch
Robert
R
Haber
Michelle
M
Norris
Murray D
MD
Lengyel
Peter
P
Hackett
Christopher S
CS
Preiss
Thomas
T
Chetcuti
Albert
A
Sullivan
Christopher S
CS
Marcusson
Eric G
EG
Weiss
William
W
L'Etoile
Noelle
N
Goga
Andrei
A
D020413:3' Untranslated Regions; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D004249:DNA Damage; D005260:Female; D005784:Gene Amplification; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology*; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D009857:Oncogenes; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000502:physiology
D020413:3' Untranslated Regions; C553224:MIRN380 microRNA, human; C459801:MYCN protein, human; D035683:MicroRNAs; C553223:Mirn380 microRNA, mouse; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D016159:Tumor Suppressor Protein p53