Circ_0000376 downregulation inhibits the progression of non-small cell lung cancer by mediating the miR-488-3p/BRD4 axis and the PI3K/PKB signaling pathway.

Abstract

The involvement of circular RNAs (circRNAs) in the development of cancers has attracted much interest. This study aimed to determine the role of circ_0000376 in non-small cell lung cancer (NSCLC) and provide a new mechanism. The expression of circ_0000376, miR-488-3p and bromodomain containing 4 (BRD4) mRNA was measured by quantitative real-time PCR (qPCR). Cell behaviors, including cell proliferation, invasion, migration, apoptosis and cell cycle progression were investigated using cell counting kit-8 (CCK-8) assay and colony formation assay, transwell assay, wound healing assay and flow cytometry assay, respectively. The putative relationship between miR-488-3p and circ_0000376 or BRD4 was verified by dual-luciferase reporter assay. The protein levels of BRD4 and phosphorylated PI3K/PKB were detected by western blot. Xenograft model was constructed to determine the role of circ_0000376 in vivo. Circ_0000376 was highly expressed in NSCLC tissues and cells. Circ_0000376 downregulation inhibited NSCLC cell proliferation, invasion and migration, promoted cell apoptosis and cell cycle arrest and slowed tumor growth in vivo. Circ_0000376 competitively bound to miR-488-3p to regulate the expression of BRD4. Rescue experiments showed that miR-488-3p deficiency reversed the effects of circ_0000376 downregulation, and miR-488-3p restoration-suppressed cell proliferation, migration and invasion were recovered by BRD4 overexpression. Moreover, circ_0000376 downregulation weakened the levels of phosphorylated PI3K and PKB, thus reducing the activity of the PI3K/PKB pathway. Circ_0000376 downregulation blocked the development of NSCLC by targeting the miR-488-3p/BRD4 network and suppressing the PI3K/PKB pathway, which broadens knowledge into the understanding of the role of circ_0000376 in NSCLC.