Notch1 promotes vasculogenic mimicry in hepatocellular carcinoma by inducing EMT signaling.
Notch1 promotes vasculogenic mimicry in hepatocellular carcinoma by inducing EMT signaling.
复制标题
Notch1通过诱导EMT信号促进肝细胞癌中的血管生成拟态
DOI：
10.18632/oncotarget.12388
复制
发表时间：
2017-01-10
期刊：
影响因子：
--
通讯作者：
Yanqing L
中科院分区：
文献类型：
--
作者：
Jue C;Lin C;Zhisheng Z;Yayun Q;Feng J;Min Z;Haibo W;Youyang S;Hisamitsu T;Shintaro I;Shiyu G;Yanqing L
高血供是肝细胞癌的主要特征之一。然而，肝癌血管生成的机制仍存在争议。在这项研究中，我们研究Notch 1在肝癌血管生成中的作用。我们发现Notch 1的表达与肿瘤标本中血管生成拟态（VM）的形成和上皮间质转化（EMT）生物标志物的表达相关。采用两种分别具有低和高Notch 1表达的肝癌细胞系HepG 2和MHCC 97-H，在体外和体内研究VM形成的机制。发现MHCC 97-H细胞在基质胶上生长时形成VM，而HepG 2细胞在基质胶上生长时不形成VM。Notch 1过表达可使HepG 2细胞获得形成VM的能力，而在MHCC 97-H细胞中敲低Notch 1表达可使细胞丧失VM形成能力。在体内研究中发现了类似的结果。Notch 1在HepG 2中的高表达促进了裸鼠异种移植物的生长，在肿瘤样品中形成了丰富的VM。此外，我们通过对临床标本、体外和体内实验模型的分析，观察到Notch 1与肝癌的EMT和恶性行为相关。TGF-β1诱导HepG 2细胞出现EMT现象，同时伴有Notch 1的激活，而Notch 1敲低的MHCC 97-H细胞对TGF-β1诱导无反应性。我们的研究结果表明，Notch 1通过激活EMT通路和形成VM促进HCC的进展。我们的研究结果将指导靶向Notch 1的新药开发。
Hypervascularity is one of the main characteristics of hepatocellular carcinoma (HCC). However, the mechanisms of angiogenesis in HCC remain controversial. In this study, we investigate the role of Notch1 in angiogenesis of HCC. We found that Notch1 expression was correlated with formation of vasculogenic mimicry (VM) and expression of biomarkers of epithelial-to-mesenchymal transition (EMT) in the tumor specimens. Two HCC cell lines, HepG2 and MHCC97-H, with low and high Notch1 expression, respectively, were used to study the mechanism of VM formation both in vitro and in vivo. It was found that MHCC97-H cells, but not HepG2 cells form VM when they grow on matrigel in vitro. HepG2 cells gained the power of forming VM when they were overexpressed with Notch1, while knockdown Notch1 expression in MHCC97-H cells led to the loss of VM forming ability of the cells. Similar results were found in in vivo study. High expression of Notch1 in HepG2 promoted xenograft growth in nude mice, with abundant VM formation in the tumor samples. Moreover, we observed Notch1 was associated with the EMT and malignant behavior of hepatocellular carcinoma by analyzing clinical specimens, models for in vitro and in vivo experiments. HepG2 presented EMT phenomenon when induced by TGF-β1, accompanied by Notch1 activation while MHCC97-H with knockdown of Notch1 lost the responsiveness to TGF-β1 induction. Our results suggest that Notch1 promotes HCC progression through activating EMT pathway and forming VM. Our results will guide targeting Notch1 in new drug development.