title: Notch1 promotes vasculogenic mimicry in hepatocellular carcinoma by inducing EMT signaling.
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.
authors.affiliation: Institution of Combining Chinese Traditional and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China.|Department of Oncology, The Second Peoples Hospital of Taizhou Affiliated to Yangzhou University, Taizhou, Jiangsu, China.|Department of Physiology, School of Medicine, Showa University, Tokyo, Japan.
authors.forename: Chen
authors.initials: C
authors.lastname: Jue
authors.affiliation: Department of Oncology, The Second Peoples Hospital of Taizhou Affiliated to Yangzhou University, Taizhou, Jiangsu, China.
authors.forename: Cui
authors.initials: C
authors.lastname: Lin
authors.affiliation: Department of Oncology, The Second Peoples Hospital of Taizhou Affiliated to Yangzhou University, Taizhou, Jiangsu, China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Zhisheng
authors.affiliation: Institution of Combining Chinese Traditional and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Yayun
authors.affiliation: Institution of Combining Chinese Traditional and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Feng
authors.affiliation: Institution of Combining Chinese Traditional and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Min
authors.affiliation: Institution of Combining Chinese Traditional and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China.
authors.forename: Wang
authors.initials: W
authors.lastname: Haibo
authors.affiliation: Institution of Combining Chinese Traditional and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China.
authors.forename: Shi
authors.initials: S
authors.lastname: Youyang
authors.affiliation: Department of Physiology, School of Medicine, Showa University, Tokyo, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Hisamitsu
authors.affiliation: Department of Physiology, School of Medicine, Showa University, Tokyo, Japan.
authors.forename: Ishikawa
authors.initials: I
authors.lastname: Shintaro
authors.affiliation: Department of Physiology, School of Medicine, Showa University, Tokyo, Japan.
authors.forename: Guo
authors.initials: G
authors.lastname: Shiyu
authors.affiliation: Institution of Combining Chinese Traditional and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Yanqing
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C497761:NOTCH1 protein, human; D051881:Receptor, Notch1
keywords: Notch1; epithelial-to-mesenchymal transition (EMT); hepatocellular carcinoma (HCC); vasculogenic mimicry (VM)