Regulation of Insulin-like Growth Factor-Mammalian Target of Rapamycin Signaling by MicroRNA in Childhood Adrenocortical Tumors

• Published in: Cancer research (Chicago, Ill.) Vol. 70; no. 11; pp. 4666 - 4675
• Main Authors: DOGHMAN, Mabrouka, EL WAKIL, Abeer, CARDINAUD, Bruno, THOMAS, Emilie, JINLING WANG, WEI ZHAO, PERALTA-DEL VALLE, Maria Helena C, FIGUEIREDO, Bonald C, ZAMBETTI, Gerard P, LALLI, Enzo
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.06.2010
• Subjects: Adrenal Cortex Neoplasms; Adrenal Cortex Neoplasms - genetics; Adrenal Cortex Neoplasms - metabolism; Adrenal Cortex Neoplasms - pathology; Adrenals. Adrenal axis. Renin-angiotensin system (diseases); Adrenocortical Adenoma; Adrenocortical Adenoma - genetics; Adrenocortical Adenoma - metabolism; Adrenocortical Adenoma - pathology; Adrenocortical Carcinoma; Adrenocortical Carcinoma - genetics; Adrenocortical Carcinoma - metabolism; Adrenocortical Carcinoma - pathology; Animals; Antineoplastic agents; Biochemistry, Molecular Biology; Biological and medical sciences; Cell Growth Processes; Cell Growth Processes - physiology; Endocrinopathies; Everolimus; Female; Humans; Intracellular Signaling Peptides and Proteins; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - metabolism; Life Sciences; Malignant tumors; Medical sciences; Mice; Mice, Inbred NOD; Mice, SCID; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Pharmacology. Drug treatments; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Protein-Serine-Threonine Kinases; Sirolimus; Sirolimus - analogs & derivatives; Sirolimus - pharmacology; Somatomedins; Somatomedins - metabolism; TOR Serine-Threonine Kinases; Transplantation, Heterologous; Tumors; Endocrinopathy; Human; Adrenal cortex carcinoma; RNA interference; Micro RNA; Malignant tumor; Gene silencing; Signal transduction; Insulin like growth factor; Adrenal gland diseases; Mammalian target of rapamycin; Child; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-09-3970

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.