Direct interaction between miR-203 and ZEB2 suppresses epithelial-mesenchymal transition signaling and reduces lung adenocarcinoma chemoresistance

Abstract

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.