title: Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors.
abstract: MicroRNAs (miRNAs) act at the posttranscriptional level to control gene expression in virtually every biological process, including oncogenesis. Here, we report the identification of a set of miRNAs that are differentially regulated in childhood adrenocortical tumors (ACT), including miR-99a and miR-100. Functional analysis of these miRNAs in ACT cell lines showed that they coordinately regulate expression of the insulin-like growth factor-mammalian target of rapamycin (mTOR)-raptor signaling pathway through binding sites in their 3'-untranslated regions. In these cells, the active Ser(2448)-phosphorylated form of mTOR is present only in mitotic cells in association with the mitotic spindle and midbody in the G(2)-M phases of the cell cycle. Pharmacologic inhibition of mTOR signaling by everolimus greatly reduces tumor cell growth in vitro and in vivo. Our results reveal a novel mechanism of regulation of mTOR signaling by miRNAs, and they lay the groundwork for clinical evaluation of drugs inhibiting the mTOR pathway for treatment of adrenocortical cancer.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, 660 route des Lucioles, 06560 Valbonne, France.
authors.forename: Mabrouka
authors.initials: M
authors.lastname: Doghman
authors.forename: Abeer
authors.initials: A
authors.lastname: El Wakil
authors.forename: Bruno
authors.initials: B
authors.lastname: Cardinaud
authors.forename: Emilie
authors.initials: E
authors.lastname: Thomas
authors.forename: Jinling
authors.initials: J
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Maria Helena C
authors.initials: MH
authors.lastname: Peralta-Del Valle
authors.forename: Bonald C
authors.initials: BC
authors.lastname: Figueiredo
authors.forename: Gerard P
authors.initials: GP
authors.lastname: Zambetti
authors.forename: Enzo
authors.initials: E
authors.lastname: Lalli
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018246:Adrenocortical Adenoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D000068338:Everolimus; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D013002:Somatomedins / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D014183:Transplantation, Heterologous
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D035683:MicroRNAs; D013002:Somatomedins; D000068338:Everolimus; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus