title: Targeting MYCN IRES in MYCN-amplified neuroblastoma with miR-375 inhibits tumor growth and sensitizes tumor cells to radiation.
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.
authors: Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Hailong
authors: H
authors: Zhang
authors: Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Tao
authors: T
authors: Liu
authors: Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Sha
authors: S
authors: Yi
authors: Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: lbgu@emory.edu.
authors: Lubing
authors: L
authors: Gu
authors: Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: mzhou@emory.edu.
authors: Muxiang
authors: M
authors: Zhou
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D015536:Down-Regulation; D016259:Genes, myc; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D011836:Radiation Tolerance / Q000235:genetics*; D012270:Ribosomes / Q000378:metabolism*
chemical_list: D020121:5' Untranslated Regions
keywords: IRES; Ionizing irradiation; MYCN; Neuroblastoma; miR-375