IL-8 suppresses E-cadherin expression in nasopharyngeal carcinoma cells by enhancing E-cadherin promoter DNA methylation.
IL-8 suppresses E-cadherin expression in nasopharyngeal carcinoma cells by enhancing E-cadherin promoter DNA methylation.
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DOI：
10.3892/ijo.2015.3226
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发表时间：
2016
影响因子：
5.2
通讯作者：
Ruili Zhang;Li-xia Peng;Jun-ping Yang;Li-Sheng Zheng;P. Xie;Meng-yao Wang;Bi-Jun Huang;Hua-rong Zhao-Hu
中科院分区：
文献类型：
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作者：
Ruili Zhang;Li-xia Peng;Jun-ping Yang;Li-Sheng Zheng;P. Xie;Meng-yao Wang;Bi-Jun Huang;Hua-rong Zhao-Hu
鼻咽癌（Nasopharyngealcarcinoma，NPC）是头颈部肿瘤中转移潜能最高的肿瘤。远处转移是治疗失败的主要原因。本实验室最近的研究表明，IL-8通过激活AKT信号通路和诱导细胞上皮间质转化（EMT）促进NPC转移。在本研究中，我们发现IL-8处理NPC细胞通过激活AKT 1通路导致DNMT 1蛋白的积累，从而导致DNMT 1蛋白的稳定。DNMT 1通过增加其启动子区域的甲基化来抑制E-cadherin的表达。LY-294002阻断IL-8诱导的p-AKT 1活化，导致DNMT 1减少和E-钙粘蛋白表达增加，而使用5-氮杂-2 '-脱氧胞苷强制去甲基化恢复E-钙粘蛋白表达。总之，我们的研究，第一次表明，IL-8/AKT 1信号通路稳定DNMT 1蛋白，从而增强了E-cadherin启动子区域的甲基化，下调E-cadherin蛋白水平在NPC细胞。在阻断IL-8/AKT通路和抑制DNMT 1后，E-钙粘蛋白表达可以逆转。这些数据表明，靶向IL-8/AKT 1信号通路和DNMT 1可能提供一种潜在的治疗方法来阻断NPC转移。
Nasopharyngeal carcinoma (NPC) has the highest metastasis potential among head and neck cancers. Distant metastasis is the major cause of treatment failure. Recent studies from our laboratory have revealed that IL-8 promotes NPC metastasis via activation of AKT signaling and induction of epithelial-mesenchymal transition (EMT) in the cells. In the present study, we found that IL-8 treatment for NPC cells resulted in an accumulation of DNMT1 protein through activating AKT1 pathway and consequent DNMT1 protein stabilization. Then DNMT1 suppressed E-cadherin expression by increasing the methylation of its promoter region. LY-294002 blocked IL-8-induced p-AKT1 activation resulting in reduction of DNMT1 and increase of E-cadherin expression, whereas forced demethylation using 5-aza-2'-deoxycytidine restored E-cadherin expression. In conclusion, our study, for the first time, shows that the IL-8/AKT1 signaling pathway stabilizes DNMT1 protein, consequently enhancing hypermethylation of E-cadherin promoter regions and downregulating E-cadherin protein level in NPC cells. Upon blockage of the IL-8/AKT pathway and inhibition of DNMT1, E-cadherin expression can be reversed. These data suggest that targeting the IL-8/AKT1 signaling pathway and DNMT1 may provide a potential therapeutic approach for blocking NPC metastasis.