Oncotarget

Research Papers:

Notch1 promotes vasculogenic mimicry in hepatocellular carcinoma by inducing EMT signaling

Chen Jue, Cui Lin, Zhang Zhisheng, Qian Yayun, Jin Feng, Zhao Min, Wang Haibo, Shi Youyang, Tadashi Hisamitsu, Ishikawa Shintaro, Guo Shiyu and Liu Yanqing _

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Oncotarget. 2017; 8:2501-2513. https://doi.org/10.18632/oncotarget.12388

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Abstract

Chen Jue1,2,3,*, Cui Lin2,*, Zhang Zhisheng2,*, Qian Yayun1, Jin Feng1, Zhao Min1, Wang Haibo1, Shi Youyang1, Tadashi Hisamitsu3, Ishikawa Shintaro3, Guo Shiyu3, Liu Yanqing1

1Institution of Combining Chinese Traditional and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China

2Department of Oncology, the Second Peoples Hospital of Taizhou affiliated to Yangzhou University, Taizhou, Jiangsu, China

3Department of Physiology, School of Medicine, Showa University, Tokyo, Japan

*These authors have contributed equally to this work

Correspondence to:

Liu Yanqing, email: liuyanqingyzu@163.com

Keywords: vasculogenic mimicry (VM), hepatocellular carcinoma (HCC), Notch1, epithelial-to-mesenchymal transition (EMT)

Received: August 02, 2016    Accepted: September 23, 2016    Published: October 1, 2016

ABSTRACT

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.


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