地西他滨通过调节miR-200/ZEB轴逆转转化生长因子-β1诱导的非小细胞肺癌上皮-间质转化。

Decitabine reverses TGF-β1-induced epithelial-mesenchymal transition in non-small-cell lung cancer by regulating miR-200/ZEB axis.

作者信息

Zhang Nan, Liu Yanyang, Wang Yuyi, Zhao Maoyuan, Tu Li, Luo Feng

机构信息

Department of Medical Oncology, Cancer Center, Lung Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.

出版信息

Drug Des Devel Ther. 2017 Mar 28;11:969-983. doi: 10.2147/DDDT.S129305. eCollection 2017.

OBJECTIVE

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.

METHODS

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.

RESULTS

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 and . 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.

CONCLUSION

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.

目的

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-β1（TGF-β1）是肿瘤发生过程中诱导EMT的重要因素。因此，针对EMT的靶向治疗可能是一种有前景的抗癌治疗方法。

方法

在本研究中，我们确定了DNA甲基转移酶抑制剂地西他滨对非小细胞肺癌（NSCLC）PC9和A549细胞中TGF-β1诱导的EMT的影响。我们还评估了miR-200/ZEB轴的参与情况。

结果

地西他滨可逆转PC9细胞中TGF-β1诱导的EMT，但对A549细胞无效。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[具体基因1]和[具体基因2]的表达来调节EMT。TGF-β1诱导miR-200启动子异常甲基化，导致PC9细胞发生EMT。地西他滨减弱了这种作用，并在体外和体内抑制肿瘤细胞迁移。然而，在A549细胞中，TGF-β1和地西他滨对miR-200启动子甲基化均无影响。