Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors.
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.
Doghman
Mabrouka
M
Institut de Pharmacologie Moléculaire et Cellulaire, 660 route des Lucioles, 06560 Valbonne, France.
El Wakil
Abeer
A
Cardinaud
Bruno
B
Thomas
Emilie
E
Wang
Jinling
J
Zhao
Wei
W
Peralta-Del Valle
Maria Helena C
MH
Figueiredo
Bonald C
BC
Zambetti
Gerard P
GP
Lalli
Enzo
E
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
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