Direct interaction between miR-203 and ZEB2 suppresses epithelial-mesenchymal transition signaling and reduces lung adenocarcinoma chemoresistance
Direct interaction between miR-203 and ZEB2 suppresses epithelial-mesenchymal transition signaling and reduces lung adenocarcinoma chemoresistance
复制标题
DOI：
10.1093/abbs/gmw099
复制
发表时间：
2016-11-01
影响因子：
3.7
通讯作者：
Luo, Rongcheng
中科院分区：
文献类型：
--
作者：
Duan, Xunhuang;Fu, Zhaojian;Luo, Rongcheng
miR-203是一种肿瘤抑制因子，参与了包括肺腺癌在内的多种肿瘤的发病机制。然而，miR-203在肺腺癌中抑制顺铂（cis-diamminedichloroplatinum; DDP）化疗耐药的作用及其分子机制仍有待确定。在这项研究中，我们发现miR-203降低了肺癌细胞的迁移和侵袭，并且增加了miR-203表达，使肺腺癌细胞对体外DDP敏感。此外，发现ZEB 2是miR-203的直接靶点，miR-203诱导上皮-间充质转化（EMT）信号。ZEB 2基因敲低可显著增加肺腺癌对DDP的化疗敏感性。更有趣的是，我们还证明了ZEB 2可以直接结合miR-203启动子的E-box并抑制其在肺腺癌中的表达。我们的数据显示，miR-203通过直接抑制上游ZEB 2基因而起负反馈作用，其抑制EMT信号传导并降低DDP的化疗耐药性。总之，这些结果突出了miR-203和ZEB 2之间的反馈回路，其参与肺腺癌的发病机制。
miR-203 is a tumor suppressor which participates in the pathogenesis of many tumors including lung adenocarcinoma. However, the role of miR-203 in suppressing chemotherapy resistance to cisplatin (cis-diamminedichloroplatinum; DDP) as well as its molecular mechanism is still to be determined in lung adenocarcinoma. In this study, we found that miR-203 decreased lung cancer cell migration and invasion, and that increased miR-203 expression sensitized lung adenocarcinoma cells to DDP in vitro. Furthermore, ZEB2 was found to be a direct target of miR-203, which induces epithelial-mesenchymal transition (EMT) signal. Knock-down of ZEB2 significantly increased DDP chemosensitivity in lung adenocarcinoma. More interestingly, we also demonstrated that ZEB2 could directly bind to E-box of the miR-203 promoter and suppress its expression in lung adenocarcinoma. Our data reveal that miR-203 serves as a negative feedback by directly suppressing the upstream ZEB2 gene, which inhibits EMT signaling and reduces chemoresistance of DDP. Together, these results highlight a feedback loop between miR-203 and ZEB2, which participates in the pathogenesis of lung adenocarcinoma.