The SNAI2-ELF3-AS1 Feedback Loop Drives Gastric Cancer Metastasis and Regulates ELF3 Expression At Transcriptional and Post-Transcriptional Levels

Abstract BackgroundThe reason for continued overexpression of SNAI2 in tumor metastasis remains largely unclear. The oncogene SNAI2 promotes tumor metastasis by regulating the expression of downstream target genes. In theory, these target genes should include not only protein-coding genes or miRNAs, but also lncRNAs. However, no lncRNA has been reported to be regulated by SNAI2 to date. MethodsRNA-seq, CHIP and dual-luciferase reporter assay were performed to identify lncRNAs regulated by SNAI2. MicroRNA-seq and RNA-seq studies were conducted to reveal the biological function of ELF3-AS1 in GC. RNA pulldown and CHIRP assays were conducted to identify the protein that interacts with ELF3-AS1. ResultsIn this study, the lncRNAs that regulated by SNAI2 were identified in gastric cancer (GC) by RNA sequencing. The ELF3 gene and its antisense lncRNA ELF3-AS1 were both transcriptionally repressed by SNAI2 or SNAI1. Down-regulation of ELF3-AS1 and ELF3 predicted poor prognosis in GC. Nuclear localized lncRNA ELF3-AS1 negatively regulated GC cell cycle progression via suppressing G1/S transition and histone synthesis. ELF3-AS1 mainly inhibited GC metastasis by repressing SNAI2 signaling. Additionally, ELF3-AS1 modulated ELF3 mRNA stability by RNA-RNA interaction. The RNA duplexes formed by ELF3 mRNA and lncRNA ELF3-AS1 directly interacted with NF45/NF90 complex. In turn, the NF45/NF90 complex dynamically regulated the expression of ELF3-AS1 and ELF3 by affecting the stability of the RNA duplex. ConclusionsThe double-negative feedback loop SNAI2-ELF3-AS1 drives GC metastasis by continuously activating SNAI2 signaling and regulates the expression of epithelial tumor suppressor ELF3 at transcriptional and post-transcriptional levels.