Department of Pancreatic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Wuhan Province, PR China; Liver Surgery Institute of Experiment Center of Medicine, Department of Hepatobiliary Surgery, Affliated Dongfeng Hospital, Hubei University of Medicine, Shiyan, Hubei 442001, PR China.
Department of Urology, Affliated Dongfeng Hospital, Hubei University of Medicine, Shiyan, Hubei 442001, PR China.
Pathol Res Pract. 2021 Apr;220:153270. doi: 10.1016/j.prp.2020.153270. Epub 2020 Dec 8.
BACKGROUND: Insufficient high-intensity focused ultrasound (HIFU) can promote the rapid progression of the residual tumor through the hypoxia inducible factor-2α +(HIF-2α)/vascular endothelial growth factor A (VEGFA)/ephrin type-A receptor 2 (EphA2) pathway. Although sorafenib has been shown to significantly improve the survival of patients with advanced liver cancer, the use of sorafenib in residual tumor tissues following HIFU has rarely been elucidated. Thus, this study aimed to investigate the potential adjuvant therapeutic effects of sorafenib following HIFU in order to reduce the relapse rate following insufficient HIFU. METHODS: Xenograft tumors were established using nude mice injected with liver cancer cells. At approximately 4 weeks after the inoculation of the tumor cells (tumors reached 1.3-1.5 cm), all mice were randomly divided into 3 groups as follows: i) The control group (no treatment); ii) the HIFU-alone group, and iii) the combination group (HIFU + sorafenib), with 6 mice per group. The residual tumor volume was determined among the different treatment groups. The protein expression levels of HIF-2α, VEGFA and EphA2 were determined by immunohistochemistry and western blotting, and the mRNA levels were detected by RT-qPCR. The microvessel density (MVD) was calculated by CD31 immunohistochemistry staining. RESULTS: The results revealed that by comparing the control group, insufficient HIFU promoted HIF-2α, VEGFA and EphA2 expression (P < 0.05). Compared with the HIFU-alone group, the protein and mRNA levels of HIF-2α, VEGFA and EphA2 were markedly decreased in the group that received combined treatment with HIFU and sorafenib (P < 0.05). Similar results were obtained for MVD expression. Synergistic tumor growth inhibitory effects were also observed between the control group and HIFU group (P < 0.05). CONCLUSIONS: The findings of this study demonstrate that the expression of HIF-2α, VEGFA and EphA2 can be inhibited by sorafenib, and that sorafenib is likely to provide an effective adjunct treatment for patients with HCC following HIFU ablation.
背景：低强度超声（HIFU）不足会通过缺氧诱导因子-2α+（HIF-2α）/血管内皮生长因子 A（VEGFA）/表皮生长因子 A 受体 2（EphA2）通路促进残余肿瘤的快速进展。虽然索拉非尼已被证明可显著改善晚期肝癌患者的生存率，但在 HIFU 后残余肿瘤组织中使用索拉非尼的情况很少被阐明。因此，本研究旨在探讨 HIFU 后索拉非尼的潜在辅助治疗效果，以降低 HIFU 不足后的复发率。
方法：使用裸鼠注射肝癌细胞建立异种移植瘤。在接种肿瘤细胞后约 4 周（肿瘤达到 1.3-1.5 cm）时，所有小鼠随机分为 3 组：i）对照组（无治疗）；ii）HIFU 组；iii）联合组（HIFU+索拉非尼），每组 6 只。比较不同治疗组的残余肿瘤体积。免疫组化和 Western blot 检测 HIF-2α、VEGFA 和 EphA2 的蛋白表达水平，RT-qPCR 检测 mRNA 水平。CD31 免疫组化染色计算微血管密度（MVD）。
结果：结果显示，与对照组相比，HIFU 不足促进了 HIF-2α、VEGFA 和 EphA2 的表达（P<0.05）。与 HIFU 组相比，联合 HIFU 和索拉非尼治疗组 HIF-2α、VEGFA 和 EphA2 的蛋白和 mRNA 水平明显降低（P<0.05）。MVD 表达也得到了类似的结果。在对照组和 HIFU 组之间也观察到协同的肿瘤生长抑制作用（P<0.05）。
结论：本研究结果表明，索拉非尼可抑制 HIF-2α、VEGFA 和 EphA2 的表达，索拉非尼可能为 HIFU 消融后 HCC 患者提供有效的辅助治疗。
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