Identification of circRNA-associated ceRNA networks in peripheral blood mononuclear cells as potential biomarkers for chronic obstructive pulmonary disease

Abstract

Abstract Chronic obstructive pulmonary disease (COPD), which is a common respiratory disorder with high morbidity and mortality globally, has a complex pathogenesis that is not fully understood. Some circular RNAs (circRNAs) have been recognized to serve as miRNA sponges for regulating target RNA transcripts during the processes of human diseases. In the present study, we aimed to investigate novel circRNA-associated biomarkers for COPD, 245 differentially expressed circRNAs were identified, including 111 up-regulated and 134 down-regulated circRNAs. These candidate circRNAs were enriched in inflammation-associated pathways (such as mTOR, B-cell receptor, and NF-κB signaling pathways) via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. A combination of two circRNAs (up-regulated hsa_circ_0067209 and down-regulated hsa_circ_0000673) demonstrated good diagnostic value (area under the receiver operating characteristic curve [AUC] = 0.866) for COPD by receiver operating characteristic curve (ROC) analysis and qRT-PCR validation. Subsequently, hsa-miR-8082 and hsa-miR-1248 were identified as targets for hsa_circ_0067209 and hsa_circ_0000673, respectively, via bioinformatics analysis and a dual-luciferase reporter assay, and the combination of these two miRNAs displayed better diagnosis potential for COPD (AUC = 0.967) than each other. Evaluation of COPD-related mRNA profiles revealed that the up-regulated genes ABR and TRPM6 were predicted downstream targets for hsa_circ_0067209/hsa-miR-8082, whereas the down-regulated gene RORC was a predicted downstream target for hsa_circ_0000673/hsa-miR-1248. In summary, hsa_circ_0067209 and hsa_circ_0000673 have potential as novel diagnostic biomarkers of COPD. In addition, competing endogenous RNA networks of hsa_circ_0067209/hsa-miR-8082/ABR/TRPM6 and hsa_circ_0000673/hsa-miR-1248/RORC may play critical regulation roles for COPD pathogenesis.