HIF-1α and HIF-2α: siblings in promoting angiogenesis of residual hepatocellular carcinoma after high-intensity focused ultrasound ablation.
HIF-1α and HIF-2α: siblings in promoting angiogenesis of residual hepatocellular carcinoma after high-intensity focused ultrasound ablation.
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DOI：
10.1371/journal.pone.0088913
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Wu L;Fu Z;Zhou S;Gong J;Liu CA;Qiao Z;Li S
高强度聚焦超声（HIFU）是一种广泛应用于治疗不能切除的肝癌的方法。然而，不足的HIFU可导致残留肿瘤的快速进展。高强度聚焦超声消融后残留肿瘤快速生长的机制尚不清楚。本研究的目的是探讨肿瘤残余血管生成的动态变化，以及HIF-1，2α在肿瘤残余血管生成中的时间效应和作用机制。通过皮下接种肝癌细胞的裸鼠（无胸腺BALB/c nu/nu小鼠）建立HepG 2细胞的异种移植瘤。接种后30天左右，除对照组外，其余小鼠均接受HIFU治疗，并按不同时间间隔（第1、3、5天（d）和第1、2、3、4周（w））随机分为7组。在不同时间点从实验组中获得残余肿瘤组织。HIF-1α、HIF-2α、VEGF-A和EphA 2的蛋白水平通过免疫组织化学分析和Western Blot测定进行定量，mRNA水平通过Q-PCR测量。免疫组化染色计数CD 31阳性血管内皮细胞，计算微血管密度。与对照组相比，HIF-1α蛋白和mRNA水平在第3天达到最高（P<0.01），随后下降（P<0.05）。HIF-2α表达于第2周达高峰（P<0.01），随后下降（P<0.05）。HIFU治疗后残余肿瘤组织中VEGF-A和EphA 2的蛋白和mRNA表达水平较对照组显著降低（P<0.01）。但在2-4周时，其水平较对照组明显升高（P<0.05）。MVD的表达也有类似的结果（P<0.05）。不充分的HIFU消融随着时间的推移促进残留癌组织中的血管生成。这些数据表明HIF-1，2α/VEGFA/EphA 2通路参与其中。
High-intensity focused ultrasound (HIFU) is a widely applied to treatment for unresectable hepatocellular carcinoma. However, insufficient HIFU can result in rapid progression of the residual tumor. The mechanism of such rapid growth of the residual tumor after HIFU ablation is poorly understood. The aim of this study was to investigate the dynamic angiogenesis of residual tumor, and the temporal effect and mechanism of the HIF-1, 2α in the residual tumor angiogenesis. Xenograft tumors of HepG2 cells were created by subcutaneously inoculating nude mice (athymic BALB/c nu/nu mice) with hepatoma cells. About thirty days after inoculation, all mice (except control group) were treated by HIFU and assigned randomly to 7 groups according to various time intervals (1st, 3rd, 5th day (d) and 1st, 2nd, 3rd, 4th week (w)). The residual tumor tissues were obtained from the experimental groups at various time points. Protein levels of HIF-1α, HIF-2α, VEGF-A, and EphA2 were quantified by immunohistochemistry analysis and Western Blot assays, and mRNA levels measured by Q-PCR. Microvascular density was calculated with counting of CD31 positive vascular endothelial cells by immunohistochemical staining. Compared with the control group, protein and mRNA levels of HIF-1α reached their highest levels on the 3rd day (P<0.01), then decreased (P<0.05). HIF-2α expression reached its highest level on the 2nd week compared with control group (P<0.01), then decreased (2w–4w) (P<0.05). The protein and mRNA levels of VEGF-A and EphA2 in the residual tumor tissues group that received HIFU were significantly decreased until 1 week compared with the control group (P<0.01). However, the levels increased compared to controls in 2–4 weeks (P<0.05). Similar results were obtained for MVD expression (P<0.05). Insufficient HIFU ablation promotes the angiogenesis in residual carcinoma tissue over time. The data indicate that the HIF-1, 2α/VEGFA/EphA2 pathway is involved.
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