Decitabine reverses TGF-β1-induced epithelial-mesenchymal transition in non-small-cell lung cancer by regulating miR-200/ZEB axis.
Decitabine reverses TGF-β1-induced epithelial-mesenchymal transition in non-small-cell lung cancer by regulating miR-200/ZEB axis.
复制标题
地西他滨通过调节 miR-200/ZEB 轴逆转 TGF-β1 诱导的非小细胞肺癌上皮间质转化
DOI：
10.2147/dddt.s129305
复制
发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Luo F
中科院分区：
文献类型：
--
作者：
Zhang N;Liu Y;Wang Y;Zhao M;Tu L;Luo F
上皮-间质转化（EMT）是肿瘤进展的关键驱动因素。肿瘤生长因子-β 1（TGF-β 1）是肿瘤发生过程中诱导EMT的重要因子。因此，靶向EMT可能是一种有前途的抗癌治疗方法。在这项研究中，我们确定了DNA甲基转移酶抑制剂地西他滨对TGF-β 1诱导的非小细胞肺癌（NSCLC）PC9和A549细胞EMT的影响。我们还评估了miR-200/ZEB轴的参与。地西他滨可逆转TGF-β 1诱导的PC 9细胞EMT，但不能逆转A549细胞EMT。这种现象与miR-200家族的表观遗传变化有关，miR-200家族通过改变ZEB1和ZEB2的表达来调节EMT。TGF-β 1诱导miR-200启动子的异常甲基化，导致PC9细胞中的EMT。地西他滨在体外和体内减弱这种作用并抑制肿瘤细胞迁移。然而，在A549细胞中，TGF-β 1和地西他滨均未对miR-200启动子甲基化产生影响。我们的研究结果表明，miR-200/ZEB轴的表观遗传调节是负责在PC 9细胞中TGF-β 1诱导EMT的原因。地西他滨通过其基于表观遗传学的治疗活性抑制NSCLC细胞PC9中的EMT。
Epithelial–mesenchymal transition (EMT) is a crucial driver of tumor progression. Tumor growth factor-beta 1 (TGF-β1) is an important factor in EMT induction in tumorigenesis. The targeting of EMT may, therefore, represent a promising approach in anticancer treatment. In this study, we determined the effect of decitabine, a DNA methyltransferase inhibitor, on TGF-β1-induced EMT in non-small-cell lung cancer (NSCLC) PC9 and A549 cells. We also assessed the involvement of the miR-200/ZEB axis. Decitabine reversed TGF-β1-induced EMT in PC9 cells, but not in A549 cells. This phenomenon was associated with epigenetic changes in the miR-200 family, which regulated EMT by altering the expression of ZEB1 and ZEB2. TGF-β1 induced aberrant methylation in miR-200 promoters, leading to EMT in PC9 cells. Decitabine attenuated this effect and inhibited tumor cell migration in vitro and in vivo. In A549 cells, however, neither TGF-β1 nor decitabine exhibited an effect on miR-200 promoter methylation. Our findings suggest that epigenetic regulation of the miR-200/ZEB axis is responsible for EMT induction by TGF-β1 in PC9 cells. Decitabine inhibits EMT in NSCLC cell PC9 through its epigenetic-based therapeutic activity.