GLOBOCAN 2020 estimates that gastric cancer (GC) with about 1.09 million new cases and 0.77 million deaths in the world. In China, the incidence and mortality of GC account for about 43.9% and 48.6% of the world [1]. Gastric adenocarcinoma (GA), also known as stomach adenocarcinoma (STAD), is caused by the malignant transformation of gastric gland epithelial cells, accounting for 95% of malignant GC cases. In recent years, the mortality of GA is gradually declining due to early detection, chemotherapy, and targeted therapy [2], [3]. However, GA is routinely diagnosed in a relatively advanced and unresectable stage, suggesting further exploration of new molecular biomarkers and potential pathogenesis mechanisms is essential for early diagnosis and advanced treatment of GA.

Circular RNA (circRNA) is a newly recognized class of special non-coding RNA (ncRNA) molecule, which is a closed circular structure formed by linking the 3’ and 5’ ends through exon cyclization or intron cyclization. Compared with linear RNA, circRNA has resistance to the degradation of RNA exonuclease, and its half-life can exceed 48 hours, which is more stable in humans [4]. circRNA is highly conserved in evolution, especially since circRNA has the microRNA (miRNA) response element, which suggests that it could interact with miRNA and abates the interaction between miRNA and 3’ Untranslated Regions (3’ UTR) of mRNA, thereby regulating the expression of target genes [5]. The majority of studies have shown that circRNA plays an important regulatory role in various cancers through the interaction of disease-related miRNA, and has great potential to become a new clinical diagnostic, treatment, and prognosis target [6]. For instance, circHERC4 could facilitate colorectal cancer cell growth and metastasis by binding to miR-556–5p and upregulating CTBP2 [7]. circCD44 repressed glioblastoma cell proliferation via the miR-326/SMAD6 and the miR-330–5p/SMAD6 pathway [8]. Furthermore, circRNA can also be involved in epigenetic regulation and protein post-translational regulation. A prior study displayed that hsa_circ_0094976 (circ_0094976) was aberrantly downregulated in GC tissues by high-throughput sequencing [9]. Nonetheless, the function and molecular mechanism of circ_0094976 in GA remain far from clear.

In this study, we identified circ_0094976, a novel circRNA derived from the ALG9 alpha-1,2-mannosyltransferase (ALG9) gene, and evaluated circ_0094976 expression in GA tissues and cells. Ectopic expression of circ_0094976 was performed to test the antitumor efficacy in vitro and in vivo. Moreover, the circ_0094976/miR-223–3p/ G protein-coupled receptor 155 (GPR155) axis was studied to provide a candidate target in GA therapy.