Abstract
Background/Aim: Gastric cancer is one of the most common malignant tumors, and its complex pathogenesis has not been fully elucidated. Circular RNAs (circRNAs) are involved in various biological processes and human diseases. However, their exact functional roles and mechanisms of action remain largely unclear. We previously discovered the differential expression of non-coding RNAs (ncRNAs) during the malignant transformation of human gastric epithelial cells. In this study, we investigated the functional roles of a significantly up-regulated circRNA (hsa_circ_0000592) in gastric cancer. Methods: N-methyl-N′-nitro-N-nitrosoguanidine (MNNG)-induced malignant-transformed gastric epithelial cells (GES-1-T) and normal gastric epithelial cells (GES-1-N) were analyzed by high-throughput circRNA sequencing. The top 15 up-regulated circRNAs in high-throughput sequencing results were further confirmed by qRT-PCR in different gastric epithelial cell lines. The function of the most significant circRNA (hsa_circ_0000592) was investigated by using RNA interference (RNAi) assays, fluorescence in situ hybridization analysis (FISH), and bioinformatics prediction methods. Results: A total of 1509 genes were up-regulated and 3142 genes were down-regulated in GES-1-T cells when compared with GES-1-N cells. When compared with GES-1-N cells, hsa_circ_0000592 was obviously up-regulated in GES-1-T cells, as well as in other gastric cancer cell lines. The silencing of hsa_circ_0000592 mRNA led to a decrease in cell proliferation, cell cycle arrest at the G0/G1 phase, an increased rate of apoptosis, and a reduction in cell migration. Furthermore, FISH showed that hsa_circ_0000592 was mainly located in the cytoplasm, and a bioinformatics analysis suggested that hsa_circ_0000592 might function by sponging multiple miRNAs, and most notably four conserved miRNAs, including miR-139-3p, miR-200, miR-367-3p, and miR-33a-3p. Conclusion: This study is the first to identify hsa_circ_0000592 as a novel circRNA with a critical role in MNNG-induced gastric cancer. Due to the essential role of hsa_circ_0000592 in gastric carcinoma cells, it may be considered as a potential biomarker for use in diagnosing gastric carcinoma. Our findings provide a new insight into the function of circRNAs in environmental carcinogen-induced gastric cancer.
Highlights
Gastric cancer is one of the most common malignant tumors
GES-1-T and normal control (GES-1-N) cells were analyzed by high-throughput circular RNA (circRNA) sequencing
The level of hsa circ 0000592 in MKN-28 cells was 11.763-fold higher than that in control GES-1-N cells (P < 0.01, Figure 2B). These results showed that hsa circ 0000592 levels were increased in both malignant-transformed GES-1-T cells and other gastric cancer cell lines, suggesting that has circ 0000592 might play an important role in the development of gastric cancer
Summary
Gastric cancer is one of the most common malignant tumors. The complex carcinogenic mechanism of gastric cancer has not been fully elucidated. Data gathered at several locations have identified some commonly encountered chemicals as risk factors for gastric cancer [2,3]; among which, N-nitroso compounds (NOCs) have received increased attention [4]. The genotoxic and carcinogenic effects of NOCs are usually attributable to their ability to damage DNA [5,6]. The monofunctional alkylating agent N-methyl-N -nitro-N-nitrosoguanidine (MNNG), one of the most common NOCs in pickled foods, is known to be a common chemical mutagen and carcinogen that directly damages DNA [11,12,13]
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