背景:癌症干细胞(CSC)是限制胃癌(GC)治疗有效性的关键因素。环状RNA(circularRNAs,circRNAs)被证实是许多癌症的重要调节因子。然而,它们在调节GC的CSC样特性中的作用仍然未知。我们的研究旨在探讨circUBA2在CSC维持中的作用及其潜在机制。
方法:我们使用circRNA微阵列分析将circUBA2鉴定为上调基因。qRT-PCR用于检测正常和GC组织中的circUBA2水平。进行体外和体内功能测定以验证circUBA2在增殖中的作用,迁移,GC细胞的转移和CSC样特性。使用生物信息学分析表征circUBA2、miR-144-5p和STC1之间的关系,双荧光报告系统,FISH,和RIP测定。
结果:CircUBA2表达在GC组织中显著增加,circUBA2高表达的GC患者预后不良。CircUBA2增强了GC的CSC样特性,从而促进细胞增殖,迁移,和转移。机械上,circUBA2通过充当miR-144-5p的海绵来上调STC1表达并进一步激活IL-6/JAK2/STAT3信号通路,从而促进GC恶性和CSC样特性。更重要的是,circUBA2增强CSC样特性的能力被托珠单抗抑制,人源化白细胞介素-6受体(IL-6R)抗体。因此,circUBA2敲低和托珠单抗协同抑制CSC样特性。
结论:我们的研究证明了circUBA2在调节GC中的CSC样性质中的关键作用。CircUBA2可能是GC的有希望的预后生物标志物。
BACKGROUND: Cancer stem cells (CSCs) are critical factors that limit the effectiveness of gastric cancer (GC) therapy. Circular RNAs (circRNAs) are confirmed as important regulators of many cancers. However, their role in regulating CSC-like properties of GC remains largely unknown. Our study aimed to investigate the role of circUBA2 in CSC maintenance and the underlying mechanisms.
METHODS: We identified circUBA2 as an upregulated gene using circRNA microarray analysis. qRT-PCR was used to examine the circUBA2 levels in normal and GC tissues. In vitro and in vivo functional assays were performed to validate the role of circUBA2 in proliferation, migration, metastasis and CSC-like properties of GC cell. The relationship between circUBA2, miR-144-5p and STC1 was characterised using bioinformatics analysis, a dual fluorescence reporter system, FISH, and RIP assays.
RESULTS: CircUBA2 expression was significantly increased in GC tissues, and patients with GC with high circUBA2 expression had a poor prognosis. CircUBA2 enhances CSC-like properties of GC, thereby promoting cell proliferation, migration, and metastasis. Mechanistically, circUBA2 promoted GC malignancy and CSC-like properties by acting as a sponge for miR-144-5p to upregulate STC1 expression and further activate the IL-6/JAK2/STAT3 signaling pathway. More importantly, the ability of circUBA2 to enhance CSC-like properties was inhibited by tocilizumab, a humanised Interleukin-6 receptor (IL-6R) antibody. Thus, circUBA2 knockdown and tocilizumab synergistically inhibited CSC-like properties.
CONCLUSIONS: Our study demonstrated the critical role of circUBA2 in regulating CSC-like properties in GC. CircUBA2 may be a promising prognostic biomarker for GC.