Reduction of RKIP expression promotes nasopharyngeal carcinoma invasion and metastasis by activating Stat3 signaling.
Reduction of RKIP expression promotes nasopharyngeal carcinoma invasion and metastasis by activating Stat3 signaling.
复制标题
RKIP表达减少通过激活Stat3信号促进鼻咽癌侵袭和转移
DOI：
10.18632/oncotarget.3847
复制
发表时间：
2015-06-30
期刊：
影响因子：
--
通讯作者：
Xiao ZQ
中科院分区：
文献类型：
--
作者：
He QY;Yi HM;Yi H;Xiao T;Qu JQ;Yuan L;Zhu JF;Li JY;Wang YY;Li LN;Feng J;Lu SS;Xiao ZQ
Raf激酶抑制蛋白（RKIP）在鼻咽癌转移中的作用及其机制尚不清楚。在此，我们发现RKIP在具有高转移潜能的NPC中下调，其下调与NPC转移和患者生存率差相关，并且是总生存率降低的独立预测因子。结合功能丧失和功能获得的方法，我们观察到RKIP的高表达降低了NPC细胞的侵袭、转移和上皮间质转化（EMT）标志物的改变。我们进一步发现RKIP过表达减弱而RKIP敲低增强NPC细胞中Stat 3的磷酸化和活化; RKIP通过与Stat 3相互作用减少Stat 3的磷酸化; Stattic减弱RKIP敲低诱导的NPC细胞迁移、侵袭和EMT标志物改变，而Stat 3过表达恢复RKIP过表达减少的NPC细胞迁移、侵袭和EMT标志物改变。此外，RKIP和磷酸化Stat 3在NPC组织中的表达与异种移植物转移呈负相关。我们的研究结果表明，RKIP是NPC转移的抑制因子，是NPC转移和预后的预测因子，RKIP下调可通过激活Stat 3信号通路促进NPC侵袭、转移和EMT，提示RKIP/Stat 3信号通路可作为NPC转移的治疗靶点。
The role and underlying mechanism of Raf kinase inhibitory protein (RKIP) in nasopharyngeal carcinoma (NPC) metastasis remain unclear. Here, we showed that RKIP was downregulated in the NPC with high metastatic potentials, and its decrement correlated with NPC metastasis and poor patient survival, and was an independent predictor for reduced overall survival. With a combination of loss-of-function and gain-of-function approaches, we observed that high expression of RKIP reduced invasion, metastasis and epithelial to mesenchymal transition (EMT) marker alternations of NPC cells. We further showed that RKIP overexpression attenuated while RKIP knockdown enhanced Stat3 phosphorylation and activation in NPC cells; RKIP reduced Stat3 phosphorylation through interacting with Stat3; Stattic attenuated NPC cell migration, invasion and EMT marker alternations induced by RKIP knockdown, whereas Stat3 overexpression restored NPC cell migration, invasion and EMT marker alternations reduced by RKIP overexpression. In addition, there was an inverse correlation between RKIP and phospho-Stat3 expression in the NPC tissues and xenograft metastases. Our data demonstrate that RKIP is a metastatic suppressor and predictor for metastasis and prognosis in NPC, and RKIP downregulation promotes NPC invasion, metastasis and EMT by activating Stat3 signaling, suggesting that RKIP/Stat3 signaling could be used as a therapeutic target for NPC metastasis.