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: Mabrouka Doghman, Abeer El Wakil, Bruno Cardinaud, Emilie Thomas, Jinling Wang, Wei Zhao, Maria Helena C Peralta-Del Valle, Bonald C Figueiredo, Gerard P Zambetti, Enzo Lalli
• Journal: Cancer research (Cancer Res) Vol. 70 Issue 11 Pg. 4666-75 (Jun 01 2010) ISSN: 1538-7445 [Electronic] United States
• PMID: 20484036 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 AACR.

Chemical References

• Intracellular Signaling Peptides and Proteins
• MicroRNAs
• Somatomedins
• Everolimus
• MTOR protein, human
• mTOR protein, mouse
• Protein Serine-Threonine Kinases
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Adrenal Cortex Neoplasms (genetics, metabolism, pathology)
• Adrenocortical Adenoma (genetics, metabolism, pathology)
• Adrenocortical Carcinoma (genetics, metabolism, pathology)
• Animals
• Cell Growth Processes (physiology)
• Everolimus
• Female
• Humans
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors, metabolism)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• MicroRNAs (genetics, metabolism)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Sirolimus (analogs & derivatives, pharmacology)
• Somatomedins (metabolism)
• TOR Serine-Threonine Kinases
• Transplantation, Heterologous