title: miR-124 inhibits cell proliferation in gastric cancer through down-regulation of SPHK1.
abstract: 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.
authors.affiliation: Laboratory of Department of Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Jintang
authors.initials: J
authors.lastname: Xia
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Wu
authors.forename: Chunping
authors.initials: C
authors.lastname: Yu
authors.forename: Weiling
authors.initials: W
authors.lastname: He
authors.forename: Haiqing
authors.initials: H
authors.lastname: Zheng
authors.forename: Yulong
authors.initials: Y
authors.lastname: He
authors.forename: Weihua
authors.initials: W
authors.lastname: Jian
authors.forename: Lianzhou
authors.initials: L
authors.lastname: Chen
authors.forename: Luanjing
authors.initials: L
authors.lastname: Zhang
authors.forename: Wen
authors.initials: W
authors.lastname: Li
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology* / Q000503:physiopathology; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D035683:MicroRNAs / Q000502:physiology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013274:Stomach Neoplasms / Q000473:pathology* / Q000503:physiopathology; D000099157:Sphingosine Kinase
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D035683:MicroRNAs; D017853:Phosphotransferases (Alcohol Group Acceptor); D051057:Proto-Oncogene Proteins c-akt; D000099157:Sphingosine Kinase; C085126:FOXO1 protein, human; C509207:MIRN124 microRNA, human