Background: Circular RNAs (circRNAs) play important regulatory roles in multiple human malignancies, including non-small cell lung cancer (NSCLC). Here, we explored the role of circRNA vacuole membrane protein 1 (circVMP1) in NSCLC progression and cisplatin (DDP) resistance.
Methods: The DDP resistance, proliferation, sphere formation ability, migration, invasion, and apoptosis of NSCLC cells were analyzed by Cell Counting Kit-8 (CCK8) assay, 5-ethynyl-2'-deoxyuridine (EdU) assay, sphere formation assay, wound healing assay, Transwell assay, and flow cytometry. Methylated RIP-qPCR (MeRIP-qPCR) was conducted to analyze the m6A modification level of SRY-box transcription factor 2 (SOX2). Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay, and RNA-pull down assay were performed to confirm the intermolecular interaction. Exosomes were identified by transmission electron microscopy (TEM) and characterized by nanoparticle tracking analysis (NTA).
Results: CircVMP1 expression was markedly elevated in DDP-resistant NSCLC cell lines compared with their parental cell lines. CircVMP1 absence restrained the proliferation, sphere formation, migration, invasion, and DDP resistance and promoted the apoptosis of DDP-resistant NSCLC cells. CircVMP1 acted as microRNA-524-5p (miR-524-5p) sponge to up-regulate the expression of methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit (METTL3) and SOX2. CircVMP1 silencing restrained the malignant behaviors and DDP resistance of A549/DDP and H1299/DDP cells by targeting miR-524-5p. Exosomal circVMP1 disseminated the malignant properties and DDP resistance to DDP-sensitive cells. Exosomal circVMP1 elevated the DDP resistance of xenograft tumors in vivo. Exosomal circVMP1 was up-regulated in the serum samples of DDP-resistant NSCLC patients compared with DDP-sensitive patients.
Conclusion: Exosome-mediated transmission of circVMP1 promoted NSCLC progression and DDP resistance by targeting miR-524-5p-METTL3/SOX2 axis.HighlightsCircVMP1 level is up-regulated in DDP-resistant NSCLC cell lines compared with DDP-sensitive cell lines.CircVMP1 absence restrains the malignant behaviors and DDP resistance of A549/DDP and H1299/DDP cells.CircVMP1-miR-524-5p/METTL3/SOX2 axis is identified for the first time.CircVMP1 plays an oncogenic role by targeting miR-524-5p-METTL3/SOX2 axis in A549/DDP and H1299/DDP cells.Exosomal circVMP1 transmits the malignant properties and DDP resistance to DDP-sensitive cells.
Keywords: METTL3; SOX2; circVMP1; cisplatin; exosome; miR-524-5p.