miR-124 inhibits cell proliferation in gastric cancer through down-regulation of SPHK1
miR-124 inhibits cell proliferation in gastric cancer through down-regulation of SPHK1
复制标题
miR-124通过下调SPHK1抑制胃癌细胞增殖
DOI：
10.1002/path.4030
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发表时间：
2012-08-01
影响因子：
7.3
通讯作者：
Li, Wen
中科院分区：
文献类型：
--
作者：
Xia, Jintang;Wu, Zhiqiang;Li, Wen
SPHK 1在胃癌中的表达升高，与患者的生存时间缩短相关。然而，SPHK 1在胃癌中上调的分子机制仍不清楚。在本研究中，我们报告了miR-124通过直接靶向其3 '-非翻译区（3'-UTR）下调SPHK 1的表达，并且miR-124的表达与胃癌样本中SPHK 1的表达呈负相关。此外，我们证明，类似于沉默SPHK 1的效果，上调miR-124在体外和体内均显著抑制胃癌细胞的增殖和致瘤性。这被发现与诱导细胞周期蛋白依赖性激酶抑制剂p21（Cip 1）和p27（Kip 1），增强FOXO 1的转录活性和抑制AKT活性的机制相关。此外，我们发现重新引入SPHK 1（不含3 '-UTR），但不含3'-UTR，可以消除miR-124介导的p21（Cip 1）和p27（Kip 1）诱导，以及挽救miR-124诱导的增殖抑制。总之，这些结果表明，miR-124在抑制胃癌中具有重要作用，并提出了一种新的miRNA介导的SPHK 1在癌细胞中表达的机制。版权所有（C）2012大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
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(Cip1) and p27(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(Cip1) and p27(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 (C) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.