Long noncoding RNA DIAPH2-AS1 promotes neural invasion of gastric cancer via stabilizing NSUN2 to enhance the m5C modification of NTN1

Abstract

Neural invasion (NI) is a vital pathological characteristic of gastric cancer (GC), which correlates with tumor recurrence and a worse prognosis. Long noncoding RNAs (lncRNAs) play critical roles in various biological processes. However, the involvement of lncRNAs in NI of GC (GC-NI) remains unclear. DIAPH2-AS1 was upregulated in NI-positive GC tissues, which was confirmed by qRT-PCR. The higher expression of DIAPH2-AS1 predicted NI and worse survival for GC patients. Both in vitro and in vivo experiments, including wound-healing assay, Transwell assay, DRG-GC cells co-culture model, the mouse sciatic nerve model, and the lung metastasis model, indicated that DIAPH2-AS1 promoted the migration, invasion, and NI potential of GC cells. Mechanistically, pulldown assay and RNA immunoprecipitation assay revealed that DIAPH2-AS1 interacted with NSUN2. Subsequent experiments indicated that DIAPH2-AS1 stabilized NSUN2 from ubiquitin-proteasomal degradation via masking the K577 and K579 of NSUN2. The protection of DIAPH2-AS1 on NSUN2 improved the stability of NTN1 mRNA via m5C modification, which finally induced GC-NI. Our work uncovered DIAPH2-AS1 as a novel oncogenic lncRNA in GC-NI and validated the DIAPH2-AS1-NSUN2-NTN1 axis as a potential therapeutic target for NI-positive GC.

Methylated lncRNAs suppress apoptosis of gastric cancer stem cells via the lncRNA–miRNA/protein axis

“…In our study, it was found that the methylated but not the unmethylated PSMA3-AS1 or MIR22HG could interact with EEF1A1 or LRPPRC protein in GCSCs. As reported, lncRNAs can exhibit diverse functional roles in the process of interactions with proteins, acting as protein decoys to recruit or sequester proteins, or functioning as scaffolds to facilitate the assembly of protein complexes [ 37 , 38 ]. Our study revealed that lncRNA methylation facilitated the interaction between lncRNA and protein to increase protein stability and further promoted tumorigenesis of GCSCs.…”

Transcriptome-wide identification of 5-methylcytosine by deaminase and reader protein-assisted sequencing

“…Numerous studies have revealed multiple molecular functions of m 5 C in numerous key stages of RNA metabolism, such as mRNA stability, translation, nuclear export 5,[9][10][11][12][13] . And the dynamic alterations of m 5 C play integral roles in many physiological and pathological processes, such as early embryonic development 14 , neurodevelopmental disorder 15,16 and multifarious tumorigenesis and migration [17][18][19][20] . Moreover, this modification significantly contributes to the regulation of gene expression 5,[9][10][11][12][13]17 .…”

Relationships of SIGLEC family-related lncRNAs with clinical prognosis and tumor immune microenvironment in ovarian cancer

“…Numerous evidence indicated that lncRNAs play an important role in several biological processes such as migration, cell division, apoptosis, differentiation, metabolism and tumorigenesis 12 . For example, Li et al 13 identified that LncRNA DIAPH2-AS1 was overexpressed in Neural invasion (NI) positive gastric cancer (GC) tissues and was substantially associated with poor prognosis of GC patients. In vitro and in vivo experiments have shown that DIAPH2-AS1 may stimulate the invasion, migration and NI potential of GC cells by regulating NSUN2-NTN1 pathway.…”