Background: Mounting evidence exhibits circRNAs as critical regulators in the progression of many tumors. The regulatory function and potential mechanism by which circ_0008126 in gastric cancer (GC) is unknown. Methods: To validate and analyze the expression levels and clinical values of circ_0008126 in GC patients, the biological phenotypes of circ_0008126 in GC were investigated in vitro and in vivo. The roles and effects of circ_0008126 on miR-502-5p, EIF4A3, and APC in GC cells were explored using rescue experiment, RNA stability assay, RNA pull-down, dual-luciferase reporter, RNA immunoprecipitation (RIP), RNA FISH, immunofluorescence (IF), and TOP/Flash and FOP/Flash assays. Results: Circ_0008126 expression levels were prominently down-regulated in GC tissues and cells. Importantly, low expression of circ_0008126 was relevant to the more lymphatic metastasis, advanced TNM stage, and poor survival period in patients with GC. Functionally, circ_0008126 inhibited GC cell proliferative activity, metastatic ability, and epithelial-mesenchymal transition (EMT) in vitro and vivo. Mechanistically, we verified that EIF4A3 can mediate the formation of circ_0008126, and circ_0008126 could competitively bind miR-502-5p and alleviate its role and effect on APC, thus inactivating the β-catenin pathway in GC. Additionally, circ_0008126 was determined to increase the stability of APC mRNA by interacting with cytoplasmic EIF4A3 protein and then enhancing the APC expression. Conclusions: These data demonstrate that EIF4A3-mediated circ_0008126 could regulate the APC expression and inactivate the β-catenin pathway partly by binding to miR-502-5p and EIF4A3, thus inhibiting the tumorigenesis and development of GC.
背景：越来越多的证据表明环状RNA（circRNA）在多种肿瘤进展中发挥关键调控作用。circ_0008126在胃癌（GC）中的调控功能及潜在机制尚不明确。方法：通过检测胃癌患者circ_0008126表达水平并分析其临床价值，结合体内外实验探究circ_0008126在胃癌中的生物学功能。采用挽救实验、RNA稳定性检测、RNA pull-down、双荧光素酶报告基因、RNA免疫沉淀（RIP）、RNA荧光原位杂交（FISH）、免疫荧光（IF）及TOP/Flash与FOP/Flash实验，系统研究circ_0008126对miR-502-5p、EIF4A3和APC的调控作用。结果：circ_0008126在胃癌组织及细胞系中表达显著下调。临床分析显示，circ_0008126低表达与胃癌患者淋巴结转移增多、TNM分期进展及不良生存期显著相关。功能实验证实，circ_0008126在体内外均能抑制胃癌细胞增殖活性、转移能力及上皮-间质转化（EMT）进程。机制研究表明：EIF4A3可介导circ_0008126环化形成；circ_0008126通过竞争性结合miR-502-5p解除其对APC的抑制作用，进而阻断β-catenin通路激活。此外，circ_0008126可通过与胞质EIF4A3蛋白相互作用增强APC mRNA稳定性，从而提升APC表达水平。结论：本研究表明，EIF4A3介导形成的circ_0008126能够通过结合miR-502-5p和EIF4A3调控APC表达并抑制β-catenin通路，从而阻碍胃癌的发生发展进程。
肿瘤(癌症)患者之家