Abstract
BACKGROUND: CircRNAs are noncoding RNA molecules that have recently been described and shown to regulate miRNA functionality. While recent studies have suggested such circRNAs to be associated with pain related diseases in humans, no comprehensive migraine-related circRNA profiles have been generated, and there is currently no clear understanding of whether they can serve as regulators of migraine pathology. METHODS: We initially conducted a circRNA microarray analysis of the plasma of migraine patients and healthy controls. Based upon these data, we then selected 8 differentially expressed circRNAs and confirmed their expression in more migraine patient plasma samples via real-time PCR. We then performed functional and pathway enrichment analyses. Lastly, using a robust rank aggregation approach, we constructed a ceRNA network according to predicted circRNA-miRNA and miRNA-mRNA pairs in these migraine patient samples. RESULTS: We were able to detect 2039 circRNAs in our patient samples, with 794 of 1245 these circRNAs being up- and downregulated in migraine patients relative to controls, respectively (fold change ≥ 1.5, p < 0.01). A qRT-PCR analysis confirmed that the expression of hsa_circRNA_100236, hsa_circRNA_102413, and hsa_circRNA_000367 was significantly enhanced in migraine patients, whereas the expression of hsa_circRNA_103809, hsa_circRNA_103670, and hsa_circRNA_101833 was significantly reduced in these individuals relative to healthy controls. We found these differentially regulated circRNAs to be associated with numerous predicted biological processes, with enrichment analyses suggesting that they may modulate the PI3K-Akt signaling so as to promote inflammation to drive migraine development. However, further research will be needed to formally test these mechanistic possibilities and to validate these circRNAs as potential biomarkers of migraine patients. CONCLUSIONS: Our results offer new potential insights into the mechanistic basis of this condition and suggest that hsa_circRNA_000367 and hsa_circRNA_102413 may offer value as regulators of migraine pathology.