Work

Elevated circASCC3 limits antitumor immunity by sponging miR-432–5p to upregulate C5a in non-small cell lung cancer

Year: 2022

Type: article

Abstract: Background: Tumor invasion and immune evasion are the main mechanisms underlying the progression of non-small-cell lung cancer (NSCLC). In addition, abnormally expressed circular RNAs (circRNAs) contribute to the malignant phenotype of NSCLC. Thus, further investigation of the mechanism of dysregulated circRNAs may provide new insight into the treatment of NSCLC.Methods: circRNA sequencing was used to explore the different expression profiles of circRNAs in 4 NSCLC tissues and paired normal tissues. Then, the expression of key circRNAs in NSCLC tissues and matched normal tissues was further evaluated via in situ hybridization and in cell lines using quantitative real-time polymerase chain reaction (qRT-PCR). Next, in vitro and in vivo models of NSCLC were employed to uncover the functions and mechanisms of key circRNAs in NSCLC progression and treatment.Results: circASCC3 (hsa_circ_0077495) was overexpressed in NSCLC tissues compared to paired normal tissues, and the upregulation of circASCC3 indicated a dismal prognosis in patients with NSCLC. Overexpressed circASCC3 enhanced the malignant phenotype of NSCLC cells in vitro and led to an immunosuppressive microenvironment in vivo. Mechanistically, circASCC3 sponged miR-432-5p to increase the expression of complement C5a, which induced the progression and dysfunctional immune status of NSCLC. Moreover, the combination of the C5aR inhibitor PMX-53 and anti-programmed cell death 1 (PD-1) antibody achieved synergistic effects in NSCLC models overexpressing circASCC3.Conclusion: These results uncover the contributions of circASCC3 to NSCLC progression and immunosuppression and provide a potential strategy for overcoming resistance to anti-PD-1 therapy.

Source: Cancer Letters

DOI: 10.1016/j.canlet.2022.215774