COE targets EphA2 to inhibit vasculogenic mimicry formation induced by hypoxia in hepatocellular carcinoma.

Background: Vasculogenic Mimicry (VM) can reduce the efficacy of anti-angiogenesis and promote distant metastasis in hepatocellular carcinoma (HCC). Our previous studies have found that Celastrus orbiculatus extract (COE) can inhibit the VM formation in HCC by reducing EphA2 expression. However the underlying mechanism related to EphA2 in VM formation is unclear. Purpose: This study aimed to confirm that EphA2 is one of the potential targets of COE, and to explore the effect of EphA2 in VM formation in hypoxia context in HCC. Methods: TCM Systems Pharmacology database and proteomics analysis were used to explore the key targets of COE in HCC treatment. CD31-PAS double staining and VE-CAD staining were used to indicate vasculogenic mimicry. The localization of EphA2 and VE-CAD was examined through fluorescent microscopy. CCK8 assay, cell invasion assay, and tube formation assay were used to indicate the formation of VM under hypoxic conditions. The regulatory relationship of EphA2 upstream and downstream molecules were evaluated through COIP and Western Blot. The nude mouse xenograft tumor models were used to observe the VM formation after knocking down or overexpressing EphA2. Results: EphA2 is identified to the target of COE, and the driving gene of HCC. In HCC surgical specimens, EphA2 expression is closely associated with the VM formation of HCC. COE-regulated EphA2 is involved in hypoxia-induced VM formation in HCC cells in vitro. EphA2 is regulated by HIF directly or indirectly by C-MYC. Overexpression of EphA2 can promote the VM formation of HCC in nude mice, while knocking down EphA2 can inhibit the VM formation. Conclusion: EphA2, as a target of COE, plays a crucial regulatory role in the formation of vasculogenic mimicry in HCC, involving upstream HIF/MYC transcriptional promotion and downstream PI3K/FAK/VE-CAD expression regulation.

[Zheng Yu-lin, a founder of the acupuncture and moxibustion cause of new China].

Mr. ZHENG Yu-lin is one of the most outstanding acupuncture scientists in the modern times in our country. He inherits the learning handed down in a family and is bold in making innovations, successfully combines the exercises to benefit the internal organs with Chinese traditional acupuncture needling methods, forming a set of unique Zheng's needling methods, which is used for treatment of severe ophthalmopathy with excellent therapeutic effects, and is famed the world over. Main achievements: took on scientific researches of acupuncture and moxibustion, teaching and clinical works in the first stage of establishment of China Academy of Traditional Chinese Medicinel trains a large number of famous specificities of acupuncture and moxibustion for new China; advocates study on channel essence; cures stubborn diseases for leaders of friend countries undertaking the great trust of the central leaders for many times, becoming an important ties of Chinese political foreign affairs.