SOX2 regulates apoptosis through MAP4K4-Survivin signaling pathway in human lung cancer cells
SOX2 regulates apoptosis through MAP4K4-Survivin signaling pathway in human lung cancer cells
复制标题
SOX2通过MAP4K4-Survivin信号通路调节人肺癌细胞凋亡
DOI：
10.1093/carcin/bgt371
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发表时间：
2014-03-01
期刊：
影响因子：
4.7
通讯作者：
Li, Na
中科院分区：
文献类型：
--
作者：
Chen, Si;Li, Xuefei;Li, Na
以往的研究表明肿瘤干细胞与肿瘤复发有关，并且发现干细胞基因SOX 2在肿瘤细胞抗凋亡中起重要作用。尽管如此，SOX 2调节细胞凋亡信号的机制仍不明确。在这里，我们证明了一个令人惊讶的发现，即SOX 2基因的沉默通过激活人非小细胞肺癌细胞中的死亡受体和线粒体信号通路有效地诱导细胞凋亡。出乎意料的是，逆转录PCR分析表明，SOX 2的下调导致先前与细胞存活有关的MAP4K4的激活。凋亡途径的评估显示，凋亡的关键诱导因子，包括肿瘤坏死因子和p53的表达增加，与生存素的同时衰减。尽管p53似乎与该途径无关，但SOX 2缺陷细胞中Survivin的丧失似乎对观察到的MAP4K4诱导的细胞死亡至关重要。拯救实验表明，SOX 2沉默介导的杀伤被Survivin的异位表达或MAP4K4表达的减少所阻断。Survivin和SOX 2在临床上的表达高度相关。结果揭示了SOX 2表达的关键靶点，并强调了MAP4K4在调节肿瘤细胞存活中的意想不到的上下文依赖性作用，MAP4K4是几种促分裂原活化蛋白激酶途径的多能激活剂。
Previous studies have implicated cancer stem cells in tumor recurrence and revealed that the stem cell gene SOX2 plays an important role in the tumor cell resistance to apoptosis. Nonetheless, the mechanism by which SOX2 regulates apoptosis signals remained undefined. Here, we demonstrated the surprising finding that silencing of the SOX2 gene effectively induces apoptosis via the activation of death receptor and mitochondrial signaling pathways in human non-small cell lung cancer cells. Unexpectedly, reverse transcriptionPCR analysis suggested that downregulation of SOX2 leads to activation of MAP4K4, previously implicated in cell survival. Evaluation of the apoptotic pathways revealed an increased expression of key inducers of apoptosis, including tumor necrosis factor- and p53, with concurrent attenuation of Survivin. Although p53 appeared dispensable for this pathway, the loss of Survivin in SOX2-deficient cells appeared critical for the observed MAP4K4 induced cell death. Rescue experiments revealed that SOX2-silencing-mediated killing was blocked by ectopic expression of Survivin, or by reduction of MAP4K4 expression. Clinically, expressions of Survivin and SOX2 were highly correlated with each other. The results reveal a key target of SOX2 expression and highlight the unexpected context-dependent role for MAP4K4, a pluripotent activator of several mitogen-activated protein kinase pathways, in regulating tumor cell survival.