Department of Biology, Faculty of Sciences, Islamic Azad University, Tehran, Iran.
Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
Life Sci. 2021 Nov 15;285:119937. doi: 10.1016/j.lfs.2021.119937. Epub 2021 Sep 8.
BACKGROUND: Secreted microRNAs (miRNAs) can serve as promising diagnostic markers for colorectal cancer (CRC). Herein, we evaluated the potential clinical significance of a signature of four circulating serum-derived miRNAs in CRC. We also demonstrated that extracellular vesicles (EVs) containing miR-221-3p could facilitate endothelial cell angiogenesis. METHODS: The expressions of four circulating serum-derived miRNAs (miR-19a-3p, miR-203-3p, miR-221-3p, and let-7f-5p) were measured by real-time quantitative PCR, and their associations with lymph node metastasis were determined in CRC patients. Receiver operating characteristic curve analysis was used to determine their diagnostic accuracy. EVs were isolated and characterized from the conditioned media of human CRC cells (HCT116 and Caco2). Cell proliferation, transwell migration, and tube formation assays were performed to investigate the pro-angiogenic effect of miR-221-3p transferred by CRC-EVs into the endothelial cells. In silico analysis was used to show the regulatory functions of miR-221-3p on SOCS3, validated by luciferase and Western blotting assays. RESULTS: The expression levels of serum-derived miR-19a-3p, miR-203-3p, miR-221-3p, and let-7f-5p were significantly higher in CRC than in healthy individuals. The expression of miR-19a-3p, miR-203-3p, and miR-221-3p were positively correlated with the lymph node metastasis status. Moreover, SOCS3 was identified as a direct target of miR-221-3p and the secreted miR-221-3p shuttled by CRC-EVs regulated STAT3/VEGFR-2 signaling axis by targeting SOCS3 in endothelial cells. CRC-EVs promoted endothelial cell proliferation, migration, and the formation of vessel-like structures. The proangiogenic effect of CRC-EVs on the cells was recapitulated by miR-221-3p overexpression, showing the importance of EVs-derived miR-221-3p in promoting endothelial cell angiogenesis. CONCLUSION: We introduced a signature of four-circulating miRNAs (miR-19a-3p, miR-203-3p, miR-221-3p, and let-7f-5p) as a novel diagnostic biomarker for CRC. Besides, we revealed that miR-221-3p induces endothelial cell angiogenesis in vitro by targeting SOCS3.
背景：分泌的 microRNAs（miRNAs）可以作为结直肠癌（CRC）有前途的诊断标志物。在此，我们评估了 CRC 中四种循环血清衍生 miRNA 特征的潜在临床意义。我们还证明了含有 miR-221-3p 的细胞外囊泡（EVs）可以促进内皮细胞血管生成。
方法：通过实时定量 PCR 测量四种循环血清衍生 miRNA（miR-19a-3p、miR-203-3p、miR-221-3p 和 let-7f-5p）的表达，并确定其与 CRC 患者淋巴结转移的关系。使用接收者操作特征曲线分析确定其诊断准确性。从人 CRC 细胞（HCT116 和 Caco2）的条件培养基中分离和表征 EVs。进行细胞增殖、Transwell 迁移和管形成测定，以研究 CRC-EVs 转染的 miR-221-3p 对内皮细胞的促血管生成作用。通过荧光素酶和 Western blot 测定验证了 miR-221-3p 对 SOCS3 的调节功能，通过计算进行了预测分析。
结果：CRC 患者血清来源的 miR-19a-3p、miR-203-3p、miR-221-3p 和 let-7f-5p 的表达水平明显高于健康个体。miR-19a-3p、miR-203-3p 和 miR-221-3p 的表达与淋巴结转移状态呈正相关。此外，SOCS3 被鉴定为 miR-221-3p 的直接靶标，并且由 CRC-EVs 分泌的 miR-221-3p 通过靶向 SOCS3 调节内皮细胞中的 STAT3/VEGFR-2 信号通路。CRC-EVs 促进内皮细胞增殖、迁移和管状结构的形成。通过 miR-221-3p 过表达再现了 CRC-EVs 对细胞的促血管生成作用，表明 EVs 衍生的 miR-221-3p 在促进内皮细胞血管生成中的重要性。
结论：我们引入了一个由四种循环 miRNA（miR-19a-3p、miR-203-3p、miR-221-3p 和 let-7f-5p）组成的特征作为 CRC 的新型诊断生物标志物。此外，我们发现 miR-221-3p 通过靶向 SOCS3 诱导内皮细胞血管生成。
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