title: Oncogenic NRAS, required for pathogenesis of embryonic rhabdomyosarcoma, relies upon the HMGA2-IGF2BP2 pathway.
abstract: Embryonic rhabdomyosarcoma (ERMS) is the most common soft-tissue tumor in children. Here, we report the identification of the minor groove DNA-binding factor high mobility group AT-hook 2 (HMGA2) as a driver of ERMS development. HMGA2 was highly expressed in normal myoblasts and ERMS cells, where its expression was essential to maintain cell proliferation, survival in vitro, and tumor outgrowth in vivo. Mechanistic investigations revealed that upregulation of the insulin-like growth factor (IGF) mRNA-binding protein IGF2BP2 was critical for HMGA2 action. In particular, IGF2BP2 was essential for mRNA and protein stability of NRAS, a frequently mutated gene in ERMS. shRNA-mediated attenuation of NRAS or pharmacologic inhibition of the MAP-ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) effector pathway showed that NRAS and NRAS-mediated signaling was required for tumor maintenance. Taken together, these findings implicate the HMGA2-IGFBP2-NRAS signaling pathway as a critical oncogenic driver in ERMS.
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. zhizhong.li@novartis.com
authors.forename: Zhizhong
authors.initials: Z
authors.lastname: Li
authors.forename: Yunyu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Krishnan
authors.initials: K
authors.lastname: Ramanujan
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.forename: David G
authors.initials: DG
authors.lastname: Kirsch
authors.forename: David J
authors.initials: DJ
authors.lastname: Glass
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D020558:GTP Phosphohydrolases / Q000502:physiology*; D025743:HMGA2 Protein / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D032446:Myoblasts / Q000737:chemistry; D016601:RNA-Binding Proteins / Q000502:physiology*; D018233:Rhabdomyosarcoma, Embryonal / Q000209:etiology* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D025743:HMGA2 Protein; C498779:IGF2BP2 protein, human; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
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