Circular RNA circFGFR1 promotes progression and anti-PD-1 resistance by sponging miR-381-3p in non-small cell lung cancer cells

Abstract

BackgroundImmune system evasion, distance tumor metastases, and increased cell proliferation are the main reasons for the progression of non-small cell lung cancer (NSCLC) and the death of NSCLC patients. Dysregulation of circular RNAs plays a critical role in the progression of NSCLC; therefore, further understanding the biological mechanisms of abnormally expressed circRNAs is critical to discovering novel, promising therapeutic targets for NSCLC treatment.MethodsThe expression of circular RNA fibroblast growth factor receptor 1 (circFGFR1) in NSCLC tissues, paired nontumor tissues, and cell lines was detected by RT-qPCR. The role of circFGFR1 in NSCLC progression was assessed both in vitro by CCK-8, clonal formation, wound healing, and Matrigel Transwell assays and in vivo by a subcutaneous tumor mouse assay. In vivo circRNA precipitation, RNA immunoprecipitation, and luciferase reporter assays were performed to explore the interaction between circFGFR1 and miR-381-3p.ResultsHere, we report that circFGFR1 is upregulated in NSCLC tissues, and circFGFR1 expression is associated with deleterious clinicopathological characteristics and poor prognoses for NSCLC patients. Forced circFGFR1 expression promoted the migration, invasion, proliferation, and immune evasion of NSCLC cells. Mechanistically, circFGFR1 could directly interact with miR-381-3p and subsequently act as a miRNA sponge to upregulate the expression of the miR-381-3p target gene C-X-C motif chemokine receptor 4 (CXCR4), which promoted NSCLC progression and resistance to anti-programmed cell death 1 (PD-1)- based therapy.ConclusionTaken together, our results suggest the critical role of circFGFR1 in the proliferation, migration, invasion, and immune evasion abilities of NSCLC cells and provide a new perspective on circRNAs during NSCLC progression.

The role of cancer-derived microRNAs in cancer immune escape

“…In addition, some miRNAs are determinates of efficacy of immune checkpoint inhibitors. Zhang et al found that circFGFR1 acted as the miRNA sponge of miR-381-3p and induced the therapeutic resistance to PD-1 blockade [147]. Besides, Nakahara et al reported that the high levels of miR-16-5p, miR-17-5p, and miR-20a-5p were the indicators of responders of melanoma patients receiving anti-PD-1 therapy [148].…”

Non-Coding RNAs in Lung Tumor Initiation and Progression

“…Altogether, these findings suggest that targeting of specific tumor initiating/suppressive genes by varying non-coding RNAs could have an effect on these immune checkpoints by mimicking the role of immune checkpoint inhibitors. Alternatively, measuring patient response to anti-PD1 therapy in NSCLCs using circRNA and circulating miRNAs has been tested as novel approaches [131,132]. With the ability of circRNA to sponge various miRNA, inducing dysregulation could measure clinical response.…”

CircRNA Expression Profile in Lung Cancer Complicated with Chronic Obstructive Pulmonary Disease Patients

“…Accumulating researches have revealed the signi cance roles of circRNA in lung cancer and COPD. For example, overexpressed circFGFR1 can promote the migration, invasion, and proliferation of NSCLC cells via sponging miR-381-3p [20]. Weimei Huang et.al performed circRNA microarray in NCI-H69 and NCI-H69AR cells and identi ed CircRNA cESRP1 as a potential prognostic biomarker in small cell lung cancer [21].…”