Abstract
In this study, we investigated whether melittin could suppress hypoxia-induced vasculogenic mimicry (VM) formation in liver cancer and explored the underlying mechanisms. Melittin significantly inhibited the proliferation of liver cancer cells with or without CoCl2 presence. Melittin also significantly inhibited CoCl2-induced migration, invasion, and VM formation of liver cancer cells. CoCl2 treatment suppressed the expression of E-cadherin and elevated the expression of N-cadherin and Vimentin. Melittin reversed the changes in the protein and mRNA levels of these epithelial-mesenchymal transition (EMT) markers. CoCl2-induced accumulation of HIF-1α increased the level of phosphorylated Akt and upregulated the expression of VEGF and MMP-2/9. Melittin decreased the HIF-1α level and thereby suppressed the levels of p-Akt, VEGF, and MMP-2/9. In addition, the inhibitor of PI3K/Akt also suppressed CoCl2-induced EMT and liver cancer cells migration, and the activator of Akt, SC-79, partly blocked the effect of melittin on CoCl2-induced EMT and liver cancer cells migration. In the xenograft tumor model in nude mice, melittin treatment significantly suppressed the tumor growth, VM formation, and HIF-1α expression in the tumor. In conclusion, this study indicates melittin may inhibit hypoxia-induced VM formation and EMT in liver cancer through inhibiting HIF-1α/Akt pathway.
Highlights
Liver cancer is one of the most common malignant tumors worldwide, especially in China
Further studies showed that melittin is able to inhibit the proliferation and migration of vascular endothelial cells and downregulate the expression of the proangiogenic factor -- vascular endothelial growth factor (VEGF) and basic fibroblast growth factor [14]. These results suggest that melittin plays an important role in the inhibition of angiogenesis and liver cancer metastasis
We first studied the effect of melittin on the viability of liver cancer cells
Summary
Liver cancer is one of the most common malignant tumors worldwide, especially in China. Metastasis is still the main cause for the treat failure and poor prognosis of liver cancer patients, even those with resectable small tumors [1]. As a typical tumor with rich blood perfusion, angiogenesis plays a crucial role in the growth, migration, and invasion of liver cancer cells. The agents targeting the angiogenesis in liver cancer have not reached original expectancy. Patients with VM show higher metastasis rate, shorter overall survival time, and worse prognosis than those without VM, and VM correlates with higher recurrence rate after liver transplantation [3, 4]. In vitro study showed that liver cancer cells with high metastatic potential are more likely to form VM than those with low metastatic potential [5]
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