Regulation of cancer stem cell properties, angiogenesis, and vasculogenic mimicry by miR-450a-5p/SOX2 axis in colorectal cancer
Regulation of cancer stem cell properties, angiogenesis, and vasculogenic mimicry by miR-450a-5p/SOX2 axis in colorectal cancer
复制标题
结直肠癌中 miR-450a-5p/SOX2 轴对癌症干细胞特性、血管生成和血管生成拟态的调节
DOI：
10.1038/s41419-020-2361-z
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发表时间：
2020-03-06
影响因子：
9
通讯作者：
Zheng, Haoxuan
中科院分区：
文献类型：
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作者：
Chen, Jiaxuan;Chen, Shengyuan;Zheng, Haoxuan
越来越多的证据表明，少数癌细胞表达干细胞标记物并具有促进恶性进展的干细胞样特性。性别决定区 Y-box2 (SOX2) 是维持癌症干细胞 (CSC) 特性所必需的干细胞转录因子。由于CSC特性与血管生成和血管生成拟态（VM）相关，因此本研究旨在全面研究SOX2是否调节结直肠癌（CRC）中的CSC特性、血管生成和VM及其潜在机制。在本研究中，在体内和体外进行了球体形成测定、流式细胞术、细胞存活分析、管形成、3D 培养、免疫印迹、小鼠模型和荧光素酶报告基因测定。通过免疫组织化学检查 CRC 组织样本中 SOX2 和 miR-450a-5p 的表达。首先，SOX2的表达不仅与不良分化和预后相关，而且还促进血管生成和VM。如功能实验中观察到的，SOX2 的敲低会停止干性特性、血管生成和 VM，同时 CD133、CD31 和 VE-钙粘蛋白的表达也会减少。研究发现 SOX2 的下调可抑制体内肿瘤发生。其次，miR-450a-5p 通过直接靶向 SOX2 的 3’UTR 区域来抑制 SOX2 的表达，从而抑制 SOX2 诱导的 CSC 特性、血管生成和 VM。此外，SOX2 过表达保留了 miR-450a-5p 诱导的对 CRC 特性、血管生成和 VM 的抑制。最后，临床样本显示 miR-450a-5p 和 SOX2 之间呈负相关。 SOX2 表达较高且 miR-450a-5p 表达较低的患者比表达相反的患者预后较差。最后，我们阐明了 miR-450a-5p-SOX2 轴在干性、血管生成和 VM 调节中的独特机制，这可能作为 CRC 的潜在治疗实践。
Growing evidence indicates that a small number of cancer cells express stem cell markers and possess stem cell-like properties that promote malignant progression. Sex-determining region Y-box2 (SOX2) is a stem cell transcription factor essential for maintaining the properties of cancer stem cell (CSC). As CSC properties have been associated with angiogenesis and vasculogenic mimicry (VM), we aimed to comprehensively investigate whether SOX2 regulates CSC properties, angiogenesis, and VM in colorectal carcinoma (CRC) and its potential mechanism in this study. For this study, sphere formation assay, flow cytometry, cell survival analysis, tube formation, 3D culture, immunoblot, mouse model, and luciferase reporter assay were performed in vivo and in vitro. Expressions of SOX2 and miR-450a-5p in CRC tissue samples were examined through immunohistochemistry. First, the expression of SOX2 was not only associated with poor differentiation and prognosis but also promoted angiogenesis and VM. Knockdown of SOX2 ceased stemness properties, angiogenesis, and VM, along with decreased expression of CD133, CD31, and VE-cadherin as observed in functional experiments. Downregulation of SOX2 was found to inhibit tumorigenesis in vivo. Second, miR-450a-5p suppressed the expression of SOX2 by targeting its 3’UTR region directly and hence restrained SOX2-induced CSC properties, angiogenesis, and VM. Moreover, SOX2 overexpression preserved the miR-450a-5p-induced inhibition of CRC properties, angiogenesis, and VM. Finally, clinical samples exhibited a negative correlation between miR-450a-5p and SOX2. Patients with higher SOX2 and lower miR-450a-5p expressions had a poorer prognosis than patients with inverse expressions. Conclusively, we elucidated a unique mechanism of miR-450a-5p-SOX2 axis in the regulation of stemness, angiogenesis, and VM, which may act as a potential therapeutic practice in CRC.