Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Cell Death Dis. 2021 Jul 5;12(7):676. doi: 10.1038/s41419-021-03911-5.
Growing evidence has indicated that circular RNAs (circRNAs) play a pivotal role as functional RNAs in diverse cancers. However, most circRNAs involved in esophageal squamous cell carcinoma (ESCC) remain undefined, and the underlying molecular mechanisms mediated by circRNAs are largely unclear. Here, we screened human circRNA expression profiles in ESCC tissues and found significantly increased expression of hsa_circ_0000277 (termed circPDE3B) in ESCC tissues and cell lines compared to the normal controls. Moreover, higher circPDE3B expression in patients with ESCC was correlated with advanced tumor-node-metastasis (TNM) stage and dismal prognosis. Functional experiments demonstrated that circPDE3B promoted the tumorigenesis and metastasis of ESCC cells in vitro and in vivo. Mechanistically, bioinformatics analysis, a dual-luciferase reporter assay, and anti-AGO2 RNA immunoprecipitation showed that circPDE3B could act as a competing endogenous RNA (ceRNA) by harboring miR-4766-5p to eliminate the inhibitory effect on the target gene laminin α1 (LAMA1). In addition, LAMA1 was significantly upregulated in ESCC tissues and was positively associated with the aggressive oncogenic phenotype. More importantly, rescue experiments revealed that the oncogenic role of circPDE3B in ESCC is partly dependent on the miR-4766-5p/LAMA1 axis. Furthermore, bioinformatics analysis combined with validation experiments showed that epithelial-mesenchymal transition (EMT) activation was involved in the oncogenic functions of the circPDE3B-miR-4766-5p/LAMA1 axis in ESCC. Taken together, we demonstrate for the first time that the circPDE3B/miR-4766-5p/LAMA1 axis functions as an oncogenic factor in promoting ESCC cell proliferation, migration, and invasion by inducing EMT, implying its potential prognostic and therapeutic significance in ESCC.
越来越多的证据表明，环状 RNA（circRNA）作为功能 RNA 在多种癌症中发挥着关键作用。然而，大多数涉及食管鳞状细胞癌（ESCC）的 circRNA 仍未被定义，circRNA 介导的潜在分子机制在很大程度上尚不清楚。在这里，我们筛选了 ESCC 组织中的人 circRNA 表达谱，发现与正常对照相比，ESCC 组织和细胞系中 hsa_circ_0000277（称为 circPDE3B）的表达显著增加。此外，ESCC 患者中更高的 circPDE3B 表达与晚期肿瘤-淋巴结-转移（TNM）分期和预后不良相关。功能实验表明，circPDE3B 促进了 ESCC 细胞在体外和体内的肿瘤发生和转移。机制上，生物信息学分析、双荧光素酶报告基因检测和抗 AGO2 RNA 免疫沉淀显示，circPDE3B 可以作为竞争性内源性 RNA（ceRNA），通过携带 miR-4766-5p 来消除对靶基因层粘连蛋白 α1（LAMA1）的抑制作用。此外，LAMA1 在 ESCC 组织中显著上调，并与侵袭性致癌表型呈正相关。更重要的是，挽救实验表明，circPDE3B 在 ESCC 中的致癌作用部分依赖于 miR-4766-5p/LAMA1 轴。此外，生物信息学分析结合验证实验表明，上皮-间充质转化（EMT）激活参与了 circPDE3B-miR-4766-5p/LAMA1 轴在 ESCC 中的致癌功能。总之，我们首次证明 circPDE3B/miR-4766-5p/LAMA1 轴通过诱导 EMT 作为一种致癌因子促进 ESCC 细胞增殖、迁移和侵袭，表明其在 ESCC 中具有潜在的预后和治疗意义。
