ZEB1-regulated lnc-Nr2f1 promotes the migration and invasion of lung adenocarcinoma cells

Numerous long non-coding RNAs (lncRNAs) are differentially expressed in cancer cells compared with normal cells and are involved in tumor progression and metastasis. Metastasis is initiated by the epithelial-to-mesenchymal transition (EMT) process, which can also be regulated by lncRNAs. Given that ZEB1 is an important transcription factor inducing EMT, we screened lncRNAs controlled by ZEB1 using RNA sequencing in murine lung adenocarcinoma cells. Among several lncRNAs regulated by ZEB1, we selected lnc-Nr2f1. Lnc-Nr2f1 is upregulated by ZEB1 and TGF-β, a potent EMT signal. Growth, migration, and invasion of lung adenocarcinoma cells were decreased after lnc-Nr2f1 knockdown and increased after lnc-Nr2f1 overexpression. Interestingly, lnc-Nr2f1 was transcriptionally controlled by NR2F1, a transcription factor that is transcribed in the antisense direction. NR2F1 was also upregulated and positively correlated with ZEB1, forming a ZEB1/NR2F1/lnc-Nr2f1 axis. Lnc-Nr2f1, in turn, promoted Twist2 transcription through direct binding to its genomic DNA region. Collectively, lnc-Nr2f1 was upregulated by ZEB1 and NR2F1, and promoted migration and invasion of lung adenocarcinoma cells via TWIST2 regulation.