MicroRNA-mediated downregulation of mTOR/FGFR3 controls tumor growth induced by Src-related oncogenic pathways

Oncogene. 2011 Aug 11;30(32):3489-501. doi: 10.1038/onc.2011.63. Epub 2011 Mar 7.

Abstract

The tyrosine kinase c-Src is upregulated in various human cancers, but the molecular mechanisms underlying c-Src-mediated tumor growth remain unclear. Here we examined the involvement of microRNAs in the c-Src-mediated tumor growth. Microarray profiling revealed that c-Src activation downregulates a limited set of microRNAs, including miR-99a, which targets oncogenic mammalian target of rapamycin (mTOR) and fibroblast growth factor receptor 3 (FGFR3). Re-expression of miR-99a suppressed tumor growth of c-Src-transformed cells, and this effect was restored by the overexpression of mTOR. The downregulation of miR-99a was also observed in epidermal growth factor- and Ras-transformed cells, and it was suppressed by inhibiting the mitogen-activated protein kinase (MAPK) pathway. Furthermore, miR-99a downregulation is associated with mTOR/FGFR3 upregulation in various human lung cancer cells/tissues. The tumorigenicity of these cells was suppressed by the introduction of miR-99a. These findings suggest that the miR-99a-mTOR/FGFR3 pathway is crucial for controlling tumor growth in a wide range of human cancers that harbor upregulation of the Src-related oncogenic pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic / genetics
  • Cells, Cultured
  • Cluster Analysis
  • Down-Regulation
  • Gene Expression Profiling
  • HEK293 Cells
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / genetics*
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Pyrimidines / pharmacology
  • RNA Interference
  • Receptor, Fibroblast Growth Factor, Type 3 / antagonists & inhibitors
  • Receptor, Fibroblast Growth Factor, Type 3 / genetics*
  • Receptor, Fibroblast Growth Factor, Type 3 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • TOR Serine-Threonine Kinases / genetics*
  • TOR Serine-Threonine Kinases / metabolism
  • src-Family Kinases / genetics*
  • src-Family Kinases / metabolism

Substances

  • MIRN99 microRNA, human
  • MicroRNAs
  • PD 173074
  • Pyrimidines
  • TOR Serine-Threonine Kinases
  • Receptor, Fibroblast Growth Factor, Type 3
  • src-Family Kinases

Associated data

  • GEO/GSE23426