Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors

Cancer Res. 2010 Jun 1;70(11):4666-75. doi: 10.1158/0008-5472.CAN-09-3970. Epub 2010 May 18.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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