Amarogentin Inhibits Liver Cancer Cell Angiogenesis after Insufficient Radiofrequency Ablation via Affecting Stemness and the p53-Dependent VEGFA/Dll4/Notch1 Pathway.

Yongchuan Zhang,Haitao Gu,Jin Wang,Yinglin Zhang,Kimimasa Tobita

doi:10.1155/2020/5391058

Abstract

Background Whether and how amarogentin suppresses the angiogenesis effect in liver cancer cells after insufficient radiofrequency ablation (iRFA) are still poorly studied. Methods The number of liver cancer stem cells (LCSCs) and the level of vascular endothelial growth factor A (VEGFA) were assessed in liver cancer tissue after iRFA. Then, CD133-positive cells were detected in iRFA models of HepG2 and Huh7 cell lines treated with amarogentin. Tube formation assays were applied to observe the antiangiogenesis effects of amarogentin. In addition, the angiogenesis-related molecules p53, delta-like ligand 4 (Dll4), and Notch1 were detected in the iRFA cells and mouse models treated with amarogentin. Results The mRNA and protein expression levels of CD133 and VEGFA were significantly higher in the residual liver cancer tissue than in the liver cancer tissues treated by hepatectomy. Amarogentin then markedly decreased the percentage of CD133-positive cells in the iRFA model in both HepG2 and Huh7 cell lines. The number of tubules formed by human umbilical vein endothelial cells (HUVECs) was significantly decreased by amarogentin. Inversely, the antiangiogenesis effect of amarogentin was counteracted after p53 silencing in the iRFA cell models. Conclusion Amarogentin prevents the malignant transformation of liver cancer after iRFA via affecting stemness and the p53-dependent VEGFA/Dll4/Notch1 pathway to inhibit cancer cell angiogenesis.

Highlights

Liver cancer is one of the most malignant cancers in the world [1]
In recent years, increasing clinical studies have confirmed that the 5-year overall survival rate of liver cancer less than 5 cm in diameter treated with radiofrequency ablation (RFA) is not inferior to that treated with hepatectomy; RFA has a lower rate of complications and is noninvasive [2]
Liu et al have revealed that liver cancer stem cells (LCSCs) induced by vascular endothelial growth factor A (VEGFA), which are produced under hypoxia and heat stimulation, accelerate the early recurrence of liver cancer after RFA treatment [5]

Summary

Background

Whether and how amarogentin suppresses the angiogenesis effect in liver cancer cells after insufficient radiofrequency ablation (iRFA) are still poorly studied. The number of liver cancer stem cells (LCSCs) and the level of vascular endothelial growth factor A (VEGFA) were assessed in liver cancer tissue after iRFA. CD133-positive cells were detected in iRFA models of HepG2 and Huh cell lines treated with amarogentin. The angiogenesis-related molecules p53, delta-like ligand 4 (Dll4), and Notch were detected in the iRFA cells and mouse models treated with amarogentin. Amarogentin markedly decreased the percentage of CD133-positive cells in the iRFA model in both HepG2 and Huh cell lines. The antiangiogenesis effect of amarogentin was counteracted after p53 silencing in the iRFA cell models. Amarogentin prevents the malignant transformation of liver cancer after iRFA via affecting stemness and the p53-dependent VEGFA/Dll4/Notch pathway to inhibit cancer cell angiogenesis

Introduction

Materials and Methods

Results

Findings

Discussion