Mi Yushuai, Zhang Dongyuan, Jiang Weiliang, Weng Junyong, Zhou Chongzhi, Huang Kejian, Tang Huamei, Yu Yang, Liu Xisheng, Cui Weiyingqi, Zhang Meng, Sun Xiaofeng, Zhou Zongguang, Peng Zhihai, Zhao Senlin, Wen Yugang
Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Gastroenterology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Cancer Lett. 2017 Mar 28;389:11-22. doi: 10.1016/j.canlet.2016.12.033. Epub 2016 Dec 30.
We previously discovered that Ras association domain family member 6 (RASSF6) was downregulated and predicted poor prognosis in GC patients. However, the mechanisms of the down regulation of RASSF6 in GC remained unclear. Increasing evidence indicates that dysregulation of microRNAs promotes the progression of cancer through the repression of tumour suppressors. Here, we identified miR-181a-5p as a novel regulator of RASSF6 in GC. Functionally, ectopic expression or silencing of miR-181a-5p, respectively, promoted or inhibited GC cell proliferation, colony formation and cell cycle transition, as well as enhanced or prevented the invasion, metastasis of GC cells and epithelial to mesenchymal transition of GC cells in vitro and in vivo. Molecularly, miR-181a-5p functioned as an onco-miRNA by activating the RASSF6-regulated MAKP pathway. Overexpression or silencing of RASSF6 could partially reverse the effects of the overexpression or repression of miR-181a-5p on GC progress caused by activation of the MAKP pathway in vitro and in vivo. Clinically, high miR-181a-5p expression predicted poor survival in GC patients, especially combined with low RASSF6 expression. Collectively, we identified miR-181a-5p as an onco-miRNA, which acts by directly repressing RASSF6 in GC.
我们先前发现，Ras关联结构域家族成员6（RASSF6）在GC患者中表达下调，并预示着不良预后。然而，GC中RASSF6下调的机制仍不清楚。越来越多的证据表明，微小RNA的失调通过抑制肿瘤抑制因子促进癌症进展。在此，我们鉴定出miR-181a-5p是GC中RASSF6的一种新型调节因子。在功能上，miR-181a-5p的异位表达或沉默分别促进或抑制GC细胞增殖、集落形成和细胞周期转变，以及在体外和体内增强或阻止GC细胞的侵袭、转移和上皮-间质转化。在分子水平上，miR-181a-5p通过激活RASSF6调控的MAKP通路发挥癌基因miRNA的作用。RASSF6的过表达或沉默可部分逆转miR-181a-5p过表达或抑制对体外和体内MAKP通路激活所致GC进展的影响。临床上，miR-181a-5p高表达预示着GC患者生存率低，尤其是与RASSF6低表达相结合时。总之，我们鉴定出miR-181a-5p是一种癌基因miRNA，它通过直接抑制GC中的RASSF6发挥作用。
