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

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. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.