miR-27a regulates endothelial differentiation of breast cancer stem like cells
miR-27a regulates endothelial differentiation of breast cancer stem like cells
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miR-27a调节乳腺癌干细胞样细胞的内皮分化
DOI：
10.1038/onc.2013.214
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发表时间：
2014-05-15
期刊：
影响因子：
8
通讯作者：
Liu, Q.
中科院分区：
文献类型：
--
作者：
Tang, W.;Yu, F.;Liu, Q.
近年来的研究表明，肿瘤干细胞具有向内皮细胞分化的能力，肿瘤内皮细胞可能来源于肿瘤干细胞。但其机制仍不清楚。我们发现血管内皮生长因子（VEGF）诱导乳腺癌干细胞样细胞（BCSLC）中内皮标志物的表达。此外，VEGF处理的BCSLCs在基质胶中形成毛细血管结构，并在组胺处理后释放vWF。VEGF处理的BCSLCs中miR-27 a的表达显著增加。在VEGF处理的BCSLC中，miR-27 a反义寡核苷酸（ASO）拮抗miR-27 a导致内皮标志物和功能降低，而在BCSLC中增加miR-27 a导致内皮特性增强。VEGF通过增加RUNX 1与miR-27 a启动子的结合来增强miR-27 a的转录。增加的miR-27 a导致ZBTB 10（一种已知的miR-27 a靶标）的表达减少。miR-27 a的表达和ZBTB 10的敲低均促进了BCSLCs体内血管生成和肿瘤转移。此外，我们证明了VEGF处理的BCSLCs分泌更多的内源性VEGF相比，未分化的BCSLCs。因此，miR-27 a通过介导BCSLCs的内皮分化促进血管生成，可能成为抗血管生成肿瘤治疗的新靶点。
Recent studies suggested that cancer stem cells (CSCs) are capable of differentiating into endothelial cells and tumor endothelium may be derived from CSCs. But the mechanism remains unclear. We showed that vascular endothelial growth factor (VEGF) induced the expression of endothelial markers in breast cancer stem like cells (BCSLCs). In addition, the VEGF-treated BCSLCs formed capillary structure in matrigel and released vWF upon histamine treatment. The miR-27a expression was significantly increased in VEGF-treated BCSLCs. Antagonizing miR-27a by miR-27a anti-sense oligos (ASOs) in VEGF-treated BCSLCs led to decreased endothelial markers and function, while increasing miR-27a in BCSLCs resulted in enhanced endothelial properties. VEGF enhanced the transcription of miR-27a by increasing RUNX1 binding to miR-27a promoter. Increased miR-27a paralleled the reduced expression of ZBTB10, a known miR-27a target. Both expression of miR-27a and knockdown of ZBTB10 in BCSLCs promoted in vivo angiogenesis and tumor metastasis. Further, we demonstrated that VEGF-treated BCSLCs secreted more endogenous VEGF compared with undifferentiated BCSLCs. Thus, miR-27a promotes angiogenesis by mediating endothelial differentiation of BCSLCs and it may be a new target for anti-angiogenesis cancer therapy.