BCL9 promotes epithelial mesenchymal transition and invasion in cisplatin resistant NSCLC cells via β-catenin pathway

Aims: Bcell lymphoma 9 (BCL9)-Wnt/beta-catenin pathway, a key signaling pathway related to epithelial-mesenchymal transition (EMT), is widely considered to be involved in invasion in various malignant tumors. However, the dysregulation of BCL9/beta-catenin pathway in non-small cell lung cancer (NSCLC) has not been revealed. This study aimed to investigate the correlation between chemotherapy resistance and BCL9/Wnt/beta-catenin signaling dysfunction. Main methods: We performed BCL9 knockdown using a lentivirus-mediated sh-RNA interference in cisplatinresistant (CR) lung cancer cells. Subsequently, the migration and invasion were determined by wound-healing and Transwell assays. Furthermore, EMT markers and beta-catenin were examined by Western blot. Immunofluorescence was used to investigate the subcellular localization of beta-catenin. The chemotherapeutic sensitivity to cisplatin in A549/DDP cell lines after treatment with BCL9 sh-RNA was estimated by MTT assay. Key findings: The knockdown of BCL9 remarkably reduced the migration and invasion abilities of A549/DDP cells. Meanwhile, nuclear translocation of beta-catenin was reduced after BCL9 was knocked down. BCL9 silencing also resulted in the downregulation of EMT-related proteins. Additionally, the wnt/beta-catenin agonist, CP21, significantly restored the expression of beta-catenin and abilities of migration and invasion in BCL9-knockdown A549/DDP cell lines. Finally, we proved that the inhibition of BCL9 could partially attenuate the stemness of cancer cells and recover the chemotherapeutic sensitivity. Significance: These findings indicated BCL9 induced the occurrence of EMT and enhancement of stemness, which resulted in cisplatin-resistance and promoted migration in NSCLC cells. Mechanically, Wnt/beta-catenin pathway is crucial in BCL9-induced migration, invasion, and chemotherapy resistance.