Mining of circular RNA database circBase revealed six potential circRNAs generated from human AGO2 gene (Fig. Mechanistically, circAGO2 physically interacts with human antigen R (HuR) protein to facilitate its competitive enrichment on the 3’-untranslated region (UTR) of target genes, resulting in reduction of AGO2 binding, repression of AGO2/miRNA-mediated gene silencing, and promotion of tumorigenesis and aggressiveness, suggesting the crucial roles of circAGO2 in cancer progression.ĬircAGO2 is up-regulated in human cancer tissues and cell lines CircAGO2 is up-regulated in human cancer tissues, associated with poor prognosis of patients, and promotes the growth, invasion, and metastasis of cancer cells. In this study, we identify one intronic circRNA generated from AGO2 gene ( circAGO2) as a novel regulator of AGO2-miRNA complexes and cancer progression. Therefore, it is crucial to understand the roles of circRNAs in cancer progression. Previous studies show that circular RNA of forkhead box O3 ( circFoxo3) represses cell cycle progression by binding to cyclin-dependent kinase 2 and cyclin-dependent kinase inhibitor 1. In addition, circRNAs may bind and sequester RNA-binding proteins (RBPs) or even base-pair with other RNAs to regulate their activities. For example, ciRS-7 is able to bind with miRNA-7 to activate oncogenes epidermal growth factor receptor ( EGFR) and v-raf-1 murine leukemia viral oncogene homolog 1 ( RAF1), resulting in aggressive phenotypes of colorectal cancer cells. One action mode of circRNAs is to serve as endogenous sponges of miRNAs to regulate target gene expression. Emerging evidence shows that circRNAs exhibit aberrant expression in many types of cancer, including gastric cancer, colorectal cancer, hepatocellular carcinoma, and ovarian cancer, and function as an important type of endogenous RNAs regulating the proliferation, migration, invasion, and therapeutic resistance of cancer cells. However, the mechanisms regulating the functions of AGO2 in tumorigenesis and aggressiveness still remain elusive.Ĭircular RNAs (circRNAs) are a class of stable RNA molecules that are covalently closed loops and resistant to the degradation by exonuclease RNase R. Recent studies have shown that AGO2 is aberrantly expressed in many types of cancer, such as gastric cancer, colorectal cancer, prostate cancer, and neuroblastoma, and regulates the proliferation, migration, and invasion of cancer cells, suggesting a compelling role of AGO2 in the development and progression of human cancers. As a unique protein of RNA-induced silencing complex (RISC) with endonuclease activity, AGO2 recognizes specific targets through base-pairing of small interfering RNA or microRNA (miRNA), resulting in degradation of mRNA or repression of translation. Taken together, these results indicate that oncogenic circAGO2 drives cancer progression through facilitating HuR-repressed functions of AGO2-miRNA complexes.Īrgonaute 2 (AGO2), a component of mammalian AGO protein family, is ubiquitously expressed and involved in post-transcriptional gene silencing. In addition, blocking the interaction between circAGO2 and HuR by cell-penetrating inhibitory peptide represses the tumorigenesis and aggressiveness of cancer cells. Pre-clinically, administration of lentivirus-mediated short hairpin RNA targeting circAGO2 inhibits the expression of downstream target genes, and suppresses the tumorigenesis and aggressiveness of xenografts in nude mice. Mechanistic studies reveal that circAGO2 physically interacts with human antigen R (HuR) protein to facilitate its activation and enrichment on the 3’-untranslated region of target genes, resulting in reduction of AGO2 binding and repression of AGO2/miRNA-mediated gene silencing associated with cancer progression. CircAGO2 promotes the growth, invasion, and metastasis of cancer cells in vitro and in vivo. CircAGO2 is up-regulated in gastric cancer, colon cancer, prostate cancer, and neuroblastoma, and is associated with poor prognosis of patients. Herein, we indentify one intronic circular RNA (circRNA) generated from AGO2 gene ( circAGO2) as a novel regulator of AGO2-miRNA complexes and cancer progression. However, the mechanisms regulating the functions of AGO2 in cancer still remain elusive. Argonaute 2 (AGO2), the core component of microRNA (miRNA)-induced silencing complex, plays a compelling role in tumorigenesis and aggressiveness.

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