COE Inhibits Vasculogenic Mimicry by Targeting EphA2 in Hepatocellular Carcinoma, a Research Based on Proteomics Analysis.

Zewen Chu,Yayun Qian,Jue Chen,Haibo Wang,Xin Shi,Xuejun He,Wei Jiang,Yanqing Liu,Li Tao,Gaoyang Chen

doi:10.3389/fphar.2021.619732

Abstract

New strategies and drugs are urgently needed to improve the treatment of hepatocellular carcinoma (HCC). Vasculogenic mimicry (VM) has been elucidated being associated with the progression of HCC and anti-VM could be a promising strategy. Celastrus orbiculatu s extract (COE), a mixture of 26 compounds isolated from the Chinese Herb Celastrus Orbiculatus Vine, has been elucidated to be able to disrupt VM formation in HCC. This study aims to dissect and identify the potential targets of COE on anti-VM formation both in vitro and in vivo that are distinct from our previous study. Proteomics analysis was used to identify differential proteins in HCC cells treated with or without COE (Data are available via ProteomeXchange with identifier PXD022203). Cells invasion was examined using Transwell. Matrigel was used to establish a 3-D culture condition for VM formation in vitro. RT-PCR and Western Blot were used to examine changes of mRNA and protein respectively. Clinical resected samples were applied to confirm association between VM formation and identified targets. Subcutaneous xenograft tumor model was established to observe tumor growth and VM formation in vivo. PAS-CD34 dual staining was used to detect VM in vivo. A total of 194 proteins were identified to be differentially expressed in HCC cells treated with or without COE. In the 93 down-regulated proteins EphA2 stood out to be regulated on both RNA and protein level. Disruption EphA2 using COE or NVP inhibited VM formation and decreased VM associated biomarkers. In xenograft mouse model, COE inhibited tumor growth and VM formation via down-regulating EphA2. Taken together, our results indicate that COE could be used in HCC treatment because of its promising anti-VM effect.

Highlights

Hepatocellular carcinoma (HCC) is a common cancer of the digestive system
We further evaluated Vasculogenic mimicry (VM) formation in MHCC97-H cells treated with NVP-BHG712, a tyrosine kinase receptor inhibitor (TKI) which could selectively bind to Erythropoietin-producing hepatocyte receptor A2 (EphA2) and block its signal (Troster et al, 2018)
Since blocking EphA2 resulted in damaging VM formation in HCC cells, we further examine the association between VM and EphA2 expression in clinical resection samples

Summary

Introduction

Hepatocellular carcinoma (HCC) is a common cancer of the digestive system. It has a high morbidity and mortality worldwide (Lu et al, 2019). Because HCC has the characteristics of rich-vascularity and high heterogeneity, patients with HCC often suffer poor prognosis and low quality of life (FerrerFabrega and Forner, 2020). Radical resection or liver transplantation is the main treatments for Proteomics Analysis on Hepatocellular Carcinoma early-stage liver cancer (Mazzaferro et al, 2020). Only 20% of the patients meet the radical treatment when newly diagnosed (Raoul and Edeline, 2020). The 5 years survival rate of HCC is only about 20% because of its invasiveness and high recurrence rate (Pinato, 2020). New strategies and drugs to improve treatment is urgently needed

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