癌症研究
蛋白激酶B
鼻咽癌
MAPK/ERK通路
PI3K/AKT/mTOR通路
小RNA
转移
MAPKAPK2地图
生物
细胞生长
激酶
尼古丁
信号转导
化学
细胞生物学
医学
癌症
MAP激酶激酶激酶
内科学
基因
神经科学
放射治疗
遗传学
生物化学
作者
Xiaojie Deng,Zhen Liu,Xiong Liu,Qiangqiang Fu,Tongyuan Deng,Juan Lü,Yiyi Liu,Zhonglin Liang,Qingping Jiang,Cheng Chen,Weiyi Fang
标识
DOI:10.1016/j.ymthe.2018.01.023
摘要
This study aimed to identify mechanisms by which microRNA 296-3p (miR-296-3p) functions as a tumor suppressor to restrain nasopharyngeal carcinoma (NPC) cell growth, metastasis, and chemoresistance. Mechanistic studies revealed that miR-296-3p negatively regulated by nicotine directly targets the oncogenic protein mitogen-activated protein kinase-activated protein kinase-2 (Mapkapk2) (MK2). Suppression of MK2 downregulated Ras/Braf/Erk/Mek/c-Myc and phosphoinositide-3-kinase (PI3K)/Akt/c-Myc signaling and promoted cytoplasmic translocation of c-Myc, which activated miR-296-3p expression by a feedback loop. This ultimately inhibited cell cycle progression, epithelial-to-mesenchymal transition (EMT), and chemoresistance of NPC. In addition, nicotine as a key component of tobacco was observed to suppress miR-296-3p and thus elevate MK2 expression by inducing PI3K/Akt/c-Myc signaling. In clinical samples, reduced miR-296-3p as an unfavorable factor was inversely correlated with MK2 and c-Myc expression. These results reveal a novel mechanism by which miR-296-3p negatively regulated by nicotine directly targets MK2-induced Ras/Braf/Erk/Mek/c-Myc or PI3K/AKT/c-Myc signaling to stimulate its own expression and suppress NPC cell proliferation and metastasis. miR-296-3p may thus serve as a therapeutic target to reverse chemotherapy resistance of NPC.
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