LncRNA ELF3-AS1 inhibits gastric cancer by forming a negative feedback loop with SNAI2 and regulates ELF3 mRNA stability via interacting with ILF2/ILF3 complex

• Published in: Journal of experimental & clinical cancer research Vol. 41; no. 1; pp. 1 - 17
• Main Authors: Li, Dandan, Shen, Li, Zhang, Xudong, Chen, Zhen, Huang, Pan, Huang, Congcong, Qin, Shanshan
• Format: Journal Article
• Language: English
• Published: London BioMed Central Ltd 02.12.2022; BioMed Central; BMC
• Subjects: Antibodies; Cancer; Cell cycle; Committees; ELF3-AS1; Gastric cancer; Gastric cancer metastasis; Gene expression; Genes; Genetic transcription; Health aspects; Laboratory animals; Medicine; Messenger RNA; Metastasis; MicroRNA; MicroRNAs; mRNA stability; Protein binding; Proteins; Research ethics; RNA sequencing; SNAI2 overexpression; Stomach cancer; Transcription factors; Transcriptional regulation; China; United States > US
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-022-02541-9

Background The biological function of lncRNA ELF3-AS1 remains largely unknown in cancers. The cause of SNAI2 overexpression in tumor metastasis remains largely unclear. The molecular mechanisms underlying the high co-expression of antisense lncRNAs and adjacent protein-coding genes remains unclear. Methods RNA-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. Results A total of 123 lncRNAs were identified to be regulated by SNAI2 in GC by RNA sequencing. The ELF3 gene and 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 the double-stranded RNA (dsRNA) binding protein complex ILF2/ILF3 (NF45/NF90). In turn, the ILF2/ILF3 complex dynamically regulated the expression of ELF3-AS1 and ELF3 by affecting the dsRNA stability. Conclusions The SNAI2-ELF3-AS1 feedback loop regulates ELF3 expression at transcriptional and post-transcriptional levels and drives gastric cancer metastasis by maintaining SNAI2 overexpression. The ILF2/ILF3 complex plays a critical role in regulating dsRNA stability. In addition, our work provides a direct evidence that head-to-head antisense lncRNAs can share promoters with neighboring coding genes, which make their expression subject to similar transcriptional regulation, leading to high co-expression. Keywords: ELF3-AS1, SNAI2 overexpression, Transcriptional regulation, mRNA stability, Gastric cancer metastasis