CircATRNL1 Facilitates Malignant Progression of Non–Small Cell Lung Cancer via the miR-103a-3p/IGFBP3/PI3K-AKT Axis

Abstract

: Background: Circular RNAs have emerged as important regulators of non-small cell lung cancer progression through competing endogenous RNA networks, but the specific role and mechanism of CircATRNL1 in NSCLC remain unclear. This study investigates the mechanistic role of CircATRNL1 in the malignant progression of non-small cell lung cancer (NSCLC). Methods: Gene expression levels in NSCLC cell lines were quantified using reverse transcription quantitative PCR (RT-qPCR). Functional assays, including Western blot analysis of epithelial– mesenchymal transition (EMT)-related proteins, wound-healing assays, and Transwell migration and invasion assays, were performed to assess the effects of CircATRNL1 on cellular motility and invasive potential. Potential RNA–RNA interactions were predicted using the ENCORI and CircBank databases, followed by luciferase reporter assays to validate these interactions experimentally. To determine whether the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway mediated the biological effects of insulin-like growth factor-binding protein 3 (IGFBP3), rescue experiments were performed using the PI3K inhibitor LY294002. Results: CircATRNL1 was significantly upregulated in NSCLC cell lines and showed typical circular RNA characteristics, including RNase R resistance and enhanced transcript stability (*** p < 0.001). CircATRNL1 knockdown inhibited NSCLC cell migration and invasion, whereas CircATRNL1 overexpression exerted the opposite effects. Mechanistically, CircATRNL1 functioned as a sponge for miR-103a-3p and relieved miR-103a-3p mediated repression of IGFBP3, as validated by luciferase reporter and rescue assays (** p < 0.01). IGFBP3 further activated PI3K/AKT signaling by increasing p-PI3K/PI3K and p-AKT/AKT ratios, while LY294002 attenuated IGFBP3-induced migration and invasion. Conclusions: CircATRNL1 promotes NSCLC cell migration and invasion by acting as a ceRNA for miR-103a-3p, thereby regulating IGFBP3 and activating PI3K/AKT signalling. These findings highlight the CircATRNL1/miR-103a-3p/IGFBP3/PI3K-AKT axis as a potential regulatory mechanism contributing to in vitro migration and invasion in NSCLC.