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

Nat Med. 2010 Oct;16(10):1134-40. doi: 10.1038/nm.2227. Epub 2010 Sep 26.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Apoptosis
  • Binding Sites
  • DNA Damage
  • Female
  • Gene Amplification*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • MicroRNAs / physiology*
  • N-Myc Proto-Oncogene Protein
  • Neuroblastoma / genetics
  • Neuroblastoma / pathology*
  • Nuclear Proteins / genetics*
  • Oncogene Proteins / genetics*
  • Oncogenes
  • Tumor Suppressor Protein p53 / antagonists & inhibitors*
  • Tumor Suppressor Protein p53 / physiology

Substances

  • 3' Untranslated Regions
  • MIRN380 microRNA, human
  • MYCN protein, human
  • MicroRNAs
  • Mirn380 microRNA, mouse
  • N-Myc Proto-Oncogene Protein
  • Nuclear Proteins
  • Oncogene Proteins
  • Tumor Suppressor Protein p53

Grant support