Abstract:Objective To investigate the effects and the mechanism of sorafenib on hepatocellular carcinoma growth and vasculogenic mimicry (VM) in mice. Methods A subcutaneous implantation mouse model of human hepatocellular carcinoma (HCC) HepG2 cells were established. Mice inoculated with HepG2 cells were randomly divided into the treatment group (sorafenib 30 mg·kg-1·d-1) and the control group by using of paired comparison method. Growth of established tumor xenografts was monitored at least twice weekly by vernier caliper measurements. VM was assessed by immunohistochemical assay and periodic acid schiff reaction (PAS) histochemical doublestaining. The expressions of HIF-1α, VEGFA, VEGFR-1 and MMP-2 in tumor tissues were also assessed by immunohistochemical assay, Western blotting and realtime quantitative PCR. Results The tumor volume in the sorafenib group was obviously decreased compared with the control group (809.69 mm3±208.71 mm3 vs 1 678.00 mm3±313.29 mm3), with a statistically significant difference (t=6.103, P=0.030). Haematoxylin and eosin (HE) staining showed that tumor tissues treated with sorafenib were characterized by obvious necrosis, but there were not the same cases in the control group. Sorafenib group significantly reduced the number of tumor functional vessel in HepG2 xenografts compared with the control group, as assessed by tumor vasculature uptake of DiOC7 (4.77±0.15 vs 8.44±0.68, t=9.192, P=0.013). The number of VM was significantly decreased by sorafenib (1.04±0.46 vs 2.66±0.42, t=4.510, P=0.041). Relative to controls, CD31positive vessels decreased after treatments (3.42±0.10 vs 1.26±0.14), with a statistically significant difference (t=21.580, P=0.002). Compared with the control group, the protein levels of HIF-1α (0.65±0.03 vs 1.00±0.00), VEGFA (0.51±0.02 vs 1.00 ±0.00), VEGFR-1 (0.45±0.04 vs 1.00±0.00) and MMP-2 (0.69±0.02 vs 1.00±0.00) were significantly decreased in the sorafenib group (t=19.650, P=0.003; t=40.493, P=0.000; t=23.429, P=0.002; t=26.071, P=0.002). Compared with the control group, the mRNA levels of HIF-1α (0.78±0.05 vs 1.00±0.00), VEGFA (0.52±0.05 vs 1.00±0.00), VEGFR-1 (0.45±0.02 vs 1.00±0.00) and MMP-2 (0.71±0.02 vs 1.00±0.00) were also significantly decreased in sorafenib group (t=6.840, P=0.021; t=27.710, P=0.001; t=62.740, P=0.000; t=23.850, P=0.002). Conclusion Sorafenib can inhibit the tumor growth and VM channels formation, which may be related with the HIF1α and VEGFA/VEGFR-1 signaling pathway.

Key words:Liver neoplasms,Aryl hydrocarbon receptor nuclear translocator,Angiogenesis inhibitors,Sorafenib,Vasculogenic mimicry