DCBLD2 Mediates Epithelial-Mesenchymal Transition-Induced Metastasis by Cisplatin in Lung Adenocarcinoma

Growing evidence suggests that cisplatin and other chemotherapeutic agents promote tumor me-tastasis while inhibiting tumor growth, which is a critical issue in clinical practices. However, the role of chemotherapeutics in promoting tumor metastasis and the molecular mechanism involved are unclear. Here, we investigated the roles of cisplatin in promoting tumor metastasis in lung adenocarcinoma (LUAD). We demonstrated that cisplatin promoted epithelial-mesenchymal transition (EMT), cell motility, and metastasis in vitro and in vivo. The bioinformatic analysis and molecular biology approaches also indicated that DCBLD2 is a key gene that mediates cispla-tin-induced metastasis. DCBLD2 stabilizes β-catenin by phosphorylating GSK3β and transporting accumulated β-catenin to the nucleus to promote the expression of EMT-related transcriptional factors (TFs), ultimately resulting in tumor metastasis. We also identified that cisplatin aggravated DCBLD2 expression by phosphorylating ERK and hence the AP-1-driven transcription of DCBLD2. Furthermore, DCBLD2-specific siRNAs encapsulated by nanocarriers prominently in-hibits cisplatin-induced metastasis in vivo. Therefore, DCBLD2 plays a key role in cispla-tin-induced metastasis in LUAD and is a potential target for preventing chemotherapy-induced metastasis in vivo. Examination of the difference of gene expression profile between A549 cells over-expressing or down-expressing DCBLD2 and empty vector cells