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

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 orbiculatus 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.

Tumor-Suppressor Gene Transmembrane Protein 98 Promotes Proliferation and Inhibits Apoptosis in Ovarian Cancer

“…Antiangiogenic drug with bevacizumab promotes a hypoxic response and vasculogenic mimicry [24], which may be related to limited efficacy and poor response to antiangiogenic therapy in OC. Angiogenesis mimicry has recently been demonstrated in a variety of human malignancies such as hepatocellular carcinoma [25], gastric cancer [26], glioblastoma [27], breast cancer [28], and head and neck cancers [29]. Vasculogenic mimicry also exists in OC, which is closely related to tumor progression and poor survival outcomes [30,31].…”

OMICS Applications for Medicinal Plants in Gastrointestinal Cancers: Current Advancements and Future Perspectives

“…Proteomics analysis identified that the expression of EphA2 was the most significantly decreased protein among 103 downregulated proteins upon COE treatment. Clinical resection of tumour tissues with VM structures from HCC patients expressed higher EphA2 than VM structure-free tissues, while blocking EphA2 by COE resulted in decreased cell invasion and damaged VM formation (Chu et al, 2021). A proteomics study revealed that three derivatives from Gamboge, namely, gambogic acid (GA), gambogenic acid (GEA) and 1,3,6,7-tetrahydroxyxanthone (TTA), inhibited HCC cell proliferation and induced apoptosis by regulating stathmin 1 (STMN1) and 14-3-3σ.…”

Physicochemical aspects of the tumour microenvironment as drivers of vasculogenic mimicry

“…It is well known that natural compounds affect multiple signalling pathways, revealing to be interesting multi-target drugs in different types of diseases. This is the case of curcumin, derived from the rhizome of Curcuma longa , and recognised as a bioactive compound responsible for numerous pharmacological activities, one of which is the suppression of VM in hepatocellular carcinoma [ 206 ]; of ginsenoside, extracted from ginseng, with anticancer activity against several types of cancers which inhibit VM through the downregulation of VE-cadherin/EphA2/MMP9/MMP2 axis [ 207 ]; of the Celastrus orbiculatus extract (COE), a mixture of 26 compounds isolated from the Chinese herb Celastrus orbiculatus vine, which has shown to have anti-cancer activity and inhibit tumour growth and VM downregulating EphA2 [ 28 ]; of niclosamide, which derives from salicylic acid, and has been used worldwide as anti-helminthic drug (for approximately 50 years) and inhibit VM through downregulation of the expression of VEGFA, MMP2, ROCK1 and Cdc42 [ 208 ]; and of triptonide, used in a wide variety of inflammatory and autoimmune disorders, isolated from the herb Tripterygium wilfordii Hook F, which inhibit VM-related gene expression (VE-cadherin and CXCL2) [ 209 ]. It is recognised that the naturally derived compounds are characterised by a wide spectrum of pharmacological activity; therefore, they could be exploited to target the multiple and pleiotropic mechanisms of activation of VM.…”

“…Being a capacity of the tumour to provide by itself sufficient blood supply for its sustainment [20], VM refers to the ability of aggressive cancer cells to produce fluid-conducting vessel-like structures in an EC-independent way [21]. First discovered in uveal melanoma in 1999 [20], during the following 20 years, VM has been reported in several malignant tumours, including melanoma [22,23], glioblastoma [24,25], osteosarcoma [26,27], hepatocellular carcinoma [28,29], and breast [30,31], lung [32,33], gastric [19,34], colorectal [35,36] and prostate [37,38] cancers. VM is associated with a high tumour grade, invasion, metastasis and poor prognosis in patients with malignant tumours [39][40][41][42][43], including breast [44], colorectal [36], prostate [45], hepatocellular [46], lung [45], ovarian [47], gastric [48] and bladder [49] cancers.…”