Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University; Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, Wenzhou, 325000, China.
Department of Pathology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
Int J Biol Sci. 2022 Feb 28;18(5):2116-2131. doi: 10.7150/ijbs.66770. eCollection 2022.
Lung adenocarcinoma (LAD) is a common malignancy; however, its underlying molecular mechanism is unclear. Circular RNAs (circRNAs) serve as significant cancer regulators. The overexpression of circRAPGEF5 in LAD tissues and cells indicated that it may be involved in promoting LAD progression. Analysis of 61 LAD tissues revealed that circRAPGEF5 was related to lymph node metastasis. Functionally, circRAPGEF5 promoted the proliferation, migration, invasion, and epithelial-mesenchymal transition of LAD cells and promoted LAD cells growth . Mechanistically, dual-luciferase reporter assays confirmed direct interaction of circRAPGEF5, miR-1236-3p, and ZEB1. miR-1236-3p was upregulated and ZEB1 expression reduced after circRAPGEF5 knockdown, and the proliferation, migration, and invasion of LAD cells was inhibited. circRAPGEF5 was significantly overexpressed in LAD cell exosomes, and co-culture experiments showed that exosomal circRAPGEF5 enhanced the metastatic ability of LAD cells. Further experiments found that serum exosomal circRAPGEF5 was overexpressed in LAD; moreover, the area under the receiver operator characteristic curve of exosomal circRAPGEF5 was superior to that of serum carcinoembryonic antigen (CEA). Jointly detected serum exosomal circRAPGEF5 and serum CEA had better diagnostic performance than when detected individually. Thus, exosomal circRAPGEF5 could promote the proliferation and metastasis of LAD via the miR-1236-3p/ZEB1 axis and serum exosomal circRAPGEF5 may serve as a promising biomarker for LAD.
肺腺癌（LAD）是一种常见的恶性肿瘤，但其潜在的分子机制尚不清楚。环状 RNA（circRNAs）作为重要的癌症调控因子。在 LAD 组织和细胞中circRAPGEF5 的过表达表明它可能参与促进 LAD 进展。对 61 例 LAD 组织的分析表明，circRAPGEF5 与淋巴结转移有关。功能上，circRAPGEF5 促进了 LAD 细胞的增殖、迁移、侵袭和上皮-间充质转化，并促进了 LAD 细胞的生长。机制上，双荧光素酶报告基因实验证实了 circRAPGEF5、miR-1236-3p 和 ZEB1 之间的直接相互作用。circRAPGEF5 敲低后，miR-1236-3p 上调，ZEB1 表达减少，LAD 细胞的增殖、迁移和侵袭受到抑制。circRAPGEF5 在 LAD 细胞外泌体中显著过表达，共培养实验表明外泌体 circRAPGEF5 增强了 LAD 细胞的转移能力。进一步的实验发现，LAD 患者血清外泌体 circRAPGEF5 过表达；此外，外泌体 circRAPGEF5 的曲线下面积优于血清癌胚抗原（CEA）。联合检测血清外泌体 circRAPGEF5 和血清 CEA 的诊断性能优于单独检测。因此，外泌体 circRAPGEF5 可通过 miR-1236-3p/ZEB1 轴促进 LAD 的增殖和转移，血清外泌体 circRAPGEF5 可能是 LAD 的一种有前途的生物标志物。
