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Mol Oncol. 2015 Aug;9(7):1301-11. doi: 10.1016/j.molonc.2015.03.005. Epub 2015 Mar 24.

Targeting MYCN IRES in MYCN-amplified neuroblastoma with miR-375 inhibits tumor growth and sensitizes tumor cells to radiation.

Author information

1
Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
2
Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: lbgu@emory.edu.
3
Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: mzhou@emory.edu.

Abstract

The MYCN oncogene is amplified in 20% of neuroblastomas, leading to its overexpression at both the mRNA and protein levels. MYCN overexpression is strongly associated with advanced disease stage, rapid tumor progression and a worse prognosis. In the present study, we identified microRNA-375 (miR-375) as a negative regulator of MYCN: enforced expression of miR-375 inhibited MYCN-amplified neuroblastoma in vitro and in vivo. Upon searching the website miRbase for possible miR-375 binding sites within the whole MYCN mRNA, we found that the MYCN 5'-UTR had significant sequence complementarity to miR-375, yet no complementary sequences existed within the MYCN 3'-UTR and coding regions. Enforced overexpression of miR-375 efficiently inhibited MYCN mRNA translation and protein synthesis, via an IRES-dependent mechanism. In athymic nude mouse model with human MYCN-amplified neuroblastoma, MYCN downregulation by miR-375 led to inhibition of tumor cell growth and tumorigenicity. In particular, miR-375-regulated inhibition of MYCN translation was enhanced when MYCN-amplified neuroblastoma cells were exposed to stress stimulation, such as ionizing irradiation (IR), resulting in a remarkable increase in the neuroblastoma's sensitivity to IR-induced cell death. Our results identified a novel mechanism by which IRES-dependent translation of MYCN is repressed by miR-375, particularly during cellular stress, highlighting a potential anticancer strategy: the development of miR-375 as a novel therapeutic agent to treat MYCN-amplified neuroblastoma.

KEYWORDS:

IRES; Ionizing irradiation; MYCN; Neuroblastoma; miR-375

PMID:
25864587
PMCID:
PMC4523463
DOI:
10.1016/j.molonc.2015.03.005
[Indexed for MEDLINE]
Free PMC Article

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