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Circ_0017639 facilitates proliferative, migratory, and invasive potential of non-small cell lung cancer (NSCLC) cells via PI3K/AKT signaling pathway.

ABSTRACT: Non-small cell lung cancer (NSCLC) has increased morbidity and mortality rate worldwide. The current NSCLS therapies are associated with poor outcomes and need further improvement. CircRNAs were shown to regulate NSCLC progression. However, little is known re garding the functions and mechanisms of circ_0017639 in NSCLC, which requires further extensive studies. The circ_0017639 expression in NSCLC tissues and cell lines was evaluated via qRT-RCR. Moreover, using ectopic plasmid incorporation and shRNA assays, we analyzed the circ_0017639-mediated cellular proliferative, migratory and invasive processes in NSCLC cell lines, using CCK-8, EdU, and transwell assays. Furthermore, the core proteins (p-PI3K, PI3K, p-AKT, and AKT) levels of the PI3K/AKT signaling cascade were investigated via immunoblotting. Finally, we tested the functional role of circ_0017639 by examining its regulation of xenograft tumor growths in nude mice in vivo. Circ_0017639 expression was remarkably high in the NSCLC tissues and cell lines. The transfection experiments showed that circ_0017639 overexpression was able to promote proliferative, migratory, and invasive properties of NSCLC cells, while sh-circ_0017639 showed opposing effects. We further showed that circ_0017639 knockdown suppressed the cellular development via PI3K/AKT cascade inactivation. Additionally, in-vivo experiment in nude mice demonstrated that sh-circ_0017639 could reduce the tumor growth of NSCLC. Circ_0017639 may promote the development of NSCLC by accelerating NSCLC metastasis through stimulating the PI3K/AKT cascade.

SUBMITTER: Zhang HB

PROVIDER: S-EPMC8805965 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:To explore the genetic and molecular events that control subclones exhibiting distinct invasive/migratory capacities derived from human epithelial ovarian cancer (EOC) cell line A2780 and SKOV3.Single-cell subclones were isolated and established that were derived from the SKOV3 and A2780 cell lines through limiting dilution methodology. Transwell insert assays and MTT assays were performed to screen and identify the subclones exhibiting the highest and the lowest invasive/migratory capacities, and the selected subclones were renamed as A-H (A2780 high), A-L (A2780 low), S-H (SKOV3 high), and S-L (SKOV3 low). Their biological characteristics were evaluated. RNA-Seq was conducted on the targeted subclones.Compared with their corresponding counterparts, A-H/S-H cells exhibited significantly higher invasive/migratory capacities (P < 0.001 and = 0.001, respectively). A-H/S-H cells displayed a clear reduction in doubling time (P = 0.004 and 0.001, respectively), and a significant increase in the percentage of cells in S phase (P = 0.004 and 0.022, respectively). Additionally, the apoptotic rates of A-H/S-H cells were significantly lower than those of A-L/S-L cells (P = 0.002 and 0.026, respectively). At both mRNA and protein levels, caspase-3 and caspase-7 expression were reduced but Bcl-2 expression was increased in A-H/S-H cells. The TrkB (anoikis-related) and Beclin1 (autophagy-related) levels were consistently high and low, respectively, in both A-H/S-H cells. Resistance to chemotherapy in vitro and higher capacities on tumor formation in vivo was presented in both A-H/S-H cells. PI3K/AKT/mTOR pathway components, PIK3CA, PIK3CD, AKT3, ECM1, GPCR, mTOR and PRKCB were increased but that the Nur77 and PTEN were decreased in A-H/S-H cells, identified by RNA-Seq and consistently confirmed by RT-PCR and Western blot analyses.Heterogeneous cell subpopulations exhibiting distinct invasive and migratory capacities co-exist within the SKOV3 and A2780 cell lines. PI3K/AKT/mTOR pathway activation is associated with higher invasive and migratory capacities in subpopulations of human ovarian cancer cell lines. Inhibiting this pathway may be useful for the chemoprevention or treatment of EOC.

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Circ_0017639 facilitates proliferative, migratory, and invasive potential of non-small cell lung cancer (NSCLC) cells via PI3K/AKT signaling pathway.

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