COE Inhibits Vasculogenic Mimicry by Targeting EphA2 in Hepatocellular Carcinoma, a Research Based on Proteomics
Zewen Chu1,2, Xin Shi1, Gaoyang Chen1
1Department of Oncology, The Second People's Hospital of Taizhou Affiliated to Medical College of Yangzhou University, Yangzhou, China.
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.
Insights
Celastrus orbiculatus extract (COE) disrupts hepatocellular carcinoma (HCC) progression by inhibiting vasculogenic mimicry (VM). This study identifies EphA2 as a key target of COE, offering a new therapeutic strategy for HCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Hepatocellular carcinoma (HCC) treatment requires novel strategies.
- Vasculogenic mimicry (VM) is a key factor in HCC progression.
- Celastrus orbiculatus extract (COE) shows potential in disrupting VM.
Purpose of the Study:
- To identify COE's molecular targets for anti-VM effects in HCC.
- To investigate COE's anti-VM mechanisms both in vitro and in vivo.
- To validate identified targets in clinical samples and animal models.
Main Methods:
- Proteomics analysis to identify differentially expressed proteins in HCC cells treated with COE.
- In vitro assays (Transwell, 3-D Matrigel culture) to assess cell invasion and VM formation.
- In vivo studies using xenograft mouse models and PAS-CD34 staining to evaluate tumor growth and VM.
- RT-PCR and Western Blot to confirm mRNA and protein level changes.
- Analysis of clinical HCC samples.
Main Results:
- Proteomics identified 194 differentially expressed proteins, with EphA2 being significantly downregulated at both RNA and protein levels.
- COE, as well as EphA2 inhibition, disrupted VM formation and reduced VM-associated biomarkers.
- In vivo, COE treatment inhibited tumor growth and VM formation by downregulating EphA2.
- Clinical samples showed a correlation between VM formation and the identified targets.
Conclusions:
- COE exhibits promising anti-VM effects in HCC by targeting EphA2.
- EphA2 is a crucial mediator of VM in HCC and a potential therapeutic target.
- COE represents a potential therapeutic agent for HCC treatment due to its anti-VM properties.
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