Abstract
Gastric cancer is the fourth leading cause of cancer-related mortality and one of the most commonly diagnosed malignancies worldwide. Gastric adenocarcinoma (GAC) accounts for the majority of gastric cancer cases. Circular RNAs (circRNAs) have been shown to be associated with carcinogenesis and cancer progression. This research aims to investigate GAC-associated circRNAs and the underlying mechanisms of circRNA-miRNA-mRNA networks in the development and progression of GAC. Differentially expressed miRNAs and mRNAs (DEMs and DEGs) were identified in Gene Expression Omnibus (GEO) microarray datasets using the R package Limma. A microarray meta-analysis was performed to identify potential GAC-associated circRNAs with high statistical power, resulting in 13 up-regulated and 19 down-regulated circRNAs. CircRNA-miRNA-mRNA networks were constructed by combining predicted and experimentally validated databases and considering differentially expressed miRNAs and mRNAs. The constructed ceRNA networks revealed the potential regulatory effect of hsa_circ_0002019 and hsa_circ_0074736 on key survival-related genes. The expression levels of these two circRNAs were measured in plasma samples from GAC patients and healthy controls using SYBR Green-based real-time PCR. Axon guidance, cellular senescence, AGE-RAGE signaling pathway in diabetic complications, and AMPK signaling pathway were among the major significant (P-value <0.05) enriched pathways of "main mRNAs" in the constructed ceRNA networks. In conclusion, we identified strongly correlated circRNAs and their likely mechanisms of action in GAC, which may improve the knowledge of regulatory networks underlying GAC formation and contribute to developing better strategies for early diagnosis, prognosis, and treatment.