A comprehensive analysis of the circRNA, miRNA, and mRNA networks reveals prognostic biomarkers for gastric cancer.

Gastric cancer (GC) remains a leading cause of cancer-related deaths worldwide. Circular RNAs (circRNAs) have been increasingly recognized for their role in GC progression, particularly by acting as competing endogenous RNAs (ceRNAs) that regulate miRNA activity. This study aimed to elucidate the regulatory mechanisms of circRNAs in GC.Differentially expressed circRNAs, miRNAs, and mRNAs were identified from Gene Expression Omnibus datasets. Functional enrichment analysis of differentially expressed genes was performed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis. A circRNA-miRNA-mRNA regulatory network was constructed based on predicted interactions. The PT-qPCR was used to detect the expression level of circRNAs in GC specimens and cell lines. The effects of hsa_circ_004228 on the GC cell functions were detected by CCK-8, Colony formation, and Transwell assay.The ceRNA network consisted of 9 core circRNAs, 10 core miRNAs, and 23 core mRNAs. Pathway analysis revealed that these mRNAs were primarily enriched in cancer-related pathways, including PI3K-Akt signaling, p53 signaling, and ECM-receptor interaction. Prognostic analysis indicated that high IER5L expression correlated with better survival, whereas high FNDC1, HTRA1, IFIT2, NDUFA4L2, and SERPINE1 expression correlated with poorer prognosis. A ceRNA prognostic subnetwork was established, incorporating 5 circRNAs (hsa_circ_0007094, hsa_circ_0007613, hsa_circ_0008768, hsa_circ_0006089, and hsa_circ_004228) and 4 miRNAs (hsa-miR-765, hsa-miR-198, hsa-miR-125a-3p, and hsa-miR-486-5p) associated with these prognostic mRNAs. The expression levels of hsa_circ_0007094, hsa_circ_0004228, hsa_circ_0007613, hsa_circ_0008768, and hsa_circ_0006089 were significantly upregulated in gastric cancer tissues. Knockdown of hsa_circ_0004228 significantly inhibits the activity, proliferation, migration, and invasion of HGC27 and AGS cells.In conclusion, we identified key circRNAs, miRNAs, and mRNAs involved in GC progression and prognosis, constructing a ceRNA network that provides novel insights into GC pathogenesis. These findings may aid in identifying potential biomarkers for GC diagnosis and prognosis.