Notch1 promotes vasculogenic mimicry in hepatocellular carcinoma by inducing EMT signaling.

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

doi:10.18632/oncotarget.12388

Notch1 promotes vasculogenic mimicry in hepatocellular carcinoma by inducing EMT signaling.

Chen Jue, Shi Youyang + Show 10 more

Open Access

https://doi.org/10.18632/oncotarget.12388

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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.

Highlights

Hepatocellular carcinoma (HCC) is the fifth most common malignant tumor with the third mortality worldwide [1]
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
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

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common malignant tumor with the third mortality worldwide [1]. It is a highly vascularized tumor required angiogenesis to grow, invade and metastasize [2]. Because of the advances in technology and clinical practice, survival yielded by resection has been improved in the last three decades. Approximate 70% cases are detected with tumor recurrence in 5 years after resection and most of these cases are present in the first 2 years [3]. Marginal anticancer effect and non-benefit in survival have been proven by a number of clinical trials [3]. Elucidation of new mechanisms underlying the disease progression and identification of therapeutic targets could contribute to improve the disease control

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