title: MiR-214 and N-ras regulatory loop suppresses rhabdomyosarcoma cell growth and xenograft tumorigenesis.
abstract: Rhabdomyosarcoma (RMS) is a childhood malignant soft tissue cancer that is derived from myogenic progenitors trapped in a permanent mode of growth. Here, we report that miR-214 is markedly down-regulated in human RMS cell lines. Although not required for embryogenesis in mice, miR-214 suppresses mouse embryonic fibroblast (MEF) proliferation. When re-introduced into RD cells, a line of human embryonal RMS cells, miR-214 showed inhibition of tumor cell growth, induction of myogenic differentiation and apoptosis, as well as suppression of colony formation and xenograft tumorigenesis. We show that in the absence of miR-214, expression of proto-oncogene N-ras is markedly elevated in miR-214(-/-) MEFs, and manipulations of miR-214 levels using microRNA mimics or inhibitor in RD cells reciprocally altered N-ras expression. We further demonstrate that forced expression of N-ras from a cDNA that lacks its 3'-untranslated region neutralized the pro-myogenic and anti-proliferative activities of miR-214. Finally, we show that N-ras is a conserved target of miR-214 in its suppression of xenograft tumor growth, and N-ras expression is up-regulated in xenograft tumor models as well as actual human RMS tissue sections. Taken together, these data indicate that miR-214 is a bona fide suppressor of human RMS tumorigensis.
authors.affiliation: Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, China.
authors.forename: Hui-jie
authors.initials: HJ
authors.lastname: Huang
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Hu
authors.initials: H
authors.lastname: Hua
authors.forename: San-en
authors.initials: SE
authors.lastname: Li
authors.forename: Jin
authors.initials: J
authors.lastname: Zhao
authors.forename: Shen
authors.initials: S
authors.lastname: Yue
authors.forename: Ting-ting
authors.initials: TT
authors.lastname: Yu
authors.forename: Yu-cui
authors.initials: YC
authors.lastname: Jin
authors.forename: Steven Y
authors.initials: SY
authors.lastname: Cheng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015139:Blotting, Southern; D015153:Blotting, Western; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D005434:Flow Cytometry; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D055786:Gene Knockout Techniques; D064593:Heterografts; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012208:Rhabdomyosarcoma / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
chemical_list: C000715470:MAS1 protein, human; C547397:MIRN214 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D000090063:Proto-Oncogene Mas; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human