Recently, growing studies have demonstrated that circular RNAs (circRNAs) function as critical players in multiple human tumors, including papillary thyroid carcinoma (PTC). However, the expression and underlying potential mechanism of circRNAs in PTC are still not fully elucidated. In this study, 14 candidate differentially expressed circRNAs (DECs) between normal thyroid tissues and benign thyroid tissues or PTC were first screened using the GSE93522 dataset by the GEO2R online tool. Then, the structural loop graphs of these 14 circRNAs were obtained through the CSCD database. After performing miRNA co-prediction by combination of CSCD and CRI databases, a potential circRNA-miRNA sub-network, consisting of 9 circRNAs and 21 miRNAs, was successfully constructed. Subsequently, the expression and prognostic values of these miRNAs were further determined by starBase, and two miRNAs, namely, miR-605-5p and miR-876-3p, were identified as key miRNAs in PTC. Then, their downstream target genes were predicted by the miRNet database. CTNNB1 and CCND1 were found to be two most potential targets of miR-876-3p by combination of multiple in silico analyses, including protein–protein interaction (PPI), hub gene screening, correlation analysis, and expression analysis. Conclusively, we established a key hsa_circ_0088494-miR-876-3p-CTNNB1/CCND1 axis linked to carcinogenesis and progression of PTC, which may provide promising therapeutic targets in treating PTC in the future.

Circular RNAs (circRNAs) and N6-methyladenosine (m 6 A) modification are extensively involved in the progression of diverse tumors, including hepatocellular carcinoma (HCC).However, the crosstalk between circRNAs and m 6 A remains elusive in the pathogenesis of HCC.Here we investigated m 6 A-mediated regulation of circRNAs in HCC. M 6 A-related circRNAs were identified by integrating information from two published studies, revealing circular cleavage and polyadenylation specific factor 6 (circCPSF6) as a novel m 6 A-modified circRNA.CircCPSF6 was dominated by ALKBH5-mediated demethylation, followed by the recognization and destabilization by YTHDF2. Meanwhile, circCPSF6 was upregulated in HCC specimens, and elevated circCPSF6 expression served as an independent prognostic factor for worse survival of HCC patients. Loss-of-function assays demonstrated that circCPSF6 maintained cell proliferation and tumorigenicity and reinforced cell motility and tumor metastasis. CircCPSF6 triggered expression of YAP1, further activating its downstream cascade. Mechanistically, circCPSF6 competitively bound PCBP2, blunting its binding to YAP1 mRNA, thereby sustaining the stability of YAP1. Functionally, removal of YAP1 reversed the effects of circCPSF6 in vitro and in vivo. Aberrant activation of the circCPSF6-YAP1 axis promoted HCC malignancy. These findings offer novel insights into the regulation of circRNAs by m 6 A modifications and the role of this epigenetic reprogramming in HCC. SignificanceThis study advances the understanding of the interplay between m 6 A methylation and circular RNAs in hepatocellular carcinoma, highlighting the potential of circCPSF6 as a therapeuticResearch.

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