miR-124 inhibits cell proliferation in gastric cancer through down-regulation of SPHK1

J Pathol. 2012 Aug;227(4):470-80. doi: 10.1002/path.4030. Epub 2012 May 23.


SPHK1 expression is elevated in gastric cancer and is associated with shorter survival times for patients. However, the molecular mechanism of SPHK1 up-regulation in gastric cancer remains unclear. In the present study, we report that miR-124 down-regulated SPHK1 expression by directly targeting its 3'-untranslated region (3'-UTR) and that miR-124 expression was inversely correlated with SPHK1 expression in gastric cancer samples. Furthermore, we demonstrated that, similar to the effect of silencing SPHK1, up-regulation of miR-124 markedly inhibited proliferation and tumourigenicity of gastric cancer cells both in vitro and in vivo. This was found to be mechanistically associated with induction of cyclin-dependent kinase inhibitors p21$^{{\rm Cip1}}$ and p27$^{{\rm Kip1}}$, enhancement of the transcriptional activity of FOXO1 and suppression of AKT activity. Moreover, we showed that the re-introduction of SPHK1 (without the 3'-UTR), but not with the 3'-UTR, could abrogate the miR-124-mediated induction of p21$^{{\rm Cip1}}$ and p27$^{{\rm Kip1}}$, as well as rescue the miR-124-induced proliferation inhibition. Together, these results suggest that miR-124 has an important role in the suppression of gastric cancer and presents a novel mechanism of miRNA-mediated SPHK1 expression in cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / pathology*
  • Adenocarcinoma / physiopathology
  • Cell Cycle / physiology
  • Cell Line, Tumor
  • Cell Proliferation*
  • Cell Transformation, Neoplastic
  • Cyclin-Dependent Kinase Inhibitor p21 / physiology
  • Cyclin-Dependent Kinase Inhibitor p27 / physiology
  • Down-Regulation / physiology*
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / physiology
  • Humans
  • In Vitro Techniques
  • MicroRNAs / physiology*
  • Phosphotransferases (Alcohol Group Acceptor) / physiology*
  • Proto-Oncogene Proteins c-akt / physiology
  • Signal Transduction / physiology
  • Stomach Neoplasms / pathology*
  • Stomach Neoplasms / physiopathology


  • Cyclin-Dependent Kinase Inhibitor p21
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • MIRN124 microRNA, human
  • MicroRNAs
  • Cyclin-Dependent Kinase Inhibitor p27
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Proto-Oncogene Proteins c-akt