Sorafenib阻断HIF-1/VEGF通路抑制超声引导下肝癌射频消融后快速进展及转移的实验研究

Ultrasound-guided radiofrequency ablation (RFA) is becoming the major approach to cure hepatocellular carcinoma, but some patients are prone to local residual after RFA. It was reported residual tumor could promote tumor rapid progression and metastasis. HIF-1/VEGF signal pathway plays an important role in tumor recurrence and metastasis, and hypoxia is an important incentive to activate this pathway. In this research, we will explore whether progression and metastasis of hepatocellular carcinoma after RFA correlate with HIF-1/VEGF pathway activated by hypoxia in tissue, and Sorafenib used as molecular targeted drug can reduce rapid progression and metastasis of hepatocellular carcinoma by blocking this pathway. In our preliminary research, we had established hepatoma cell hypoxia model and confirmed Sorafenib could inhibited HIF-1 expression in vitro. Now, we further verify the impact of sorafenib on hepatoma cell in hypoxia status. In vivo test, we took radiofrequency ablation guided by ultrasound on tumor tissue, then detected molecular biology index and quantitatively analysed contrast enhanced ultrasound, through which we could confirm the inhibitive effect of sorafenib on tumor progression and metastasis, also its impact on microvessel. Our research can clarify the mechanism of RFA inducing rapid progression and metastasis of hepatocellular carcinoma, and provide theoretical basis for Sorafenib reducing tumor rapid progression and metastasis after RFA.

超声引导下射频消融(RFA)已成为肝癌主要治疗手段，但消融后部分患者易发生局部残留，据报道残余瘤可促进肿瘤快速进展及转移。HIF-1/VEGF通路在肝癌复发转移中起重要作用，缺氧是其激活重要诱因。本研究拟探讨肝癌RFA后进展转移是否与治疗中组织缺氧致HIF-1/VEGF通路激活有关及分子靶向药物Sorafenib是否作用于该通路而降低肝癌复发转移。我们前期已建立肝癌细胞缺氧模型并体外实验证实Sorafenib可抑制HIF-1表达，本研究拟进一步验证Sorafenib对缺氧状态肝癌细胞影响；并通过动物试验，行超声引导下射频消融，通过对瘤体分子生物学检测及超声造影定量分析，验证Sorafenib对肝癌裸鼠原位移植瘤RFA后进展、转移的抑制作用，及对微血管生成的影响。通过本研究为阐明RFA导致肝癌快速进展及转移的作用机制，及Sorafenib应用于RFA术后患者以降低进展转移提供理论上的依据。

超声引导下肝癌射频消融(Radiofrequency ablation, RFA)术后部分患者易发生局部残留，据报道残余瘤可促进肿瘤快速进展及转移。HIF-1/VEGF通路在肝癌复发转移中起重要作用，缺氧是其激活重要诱因。本研究按照计划顺利完成，探讨肝癌 RFA 后进展转移是否与治疗中组织缺氧致 HIF-1/VEGF通路激活有关及分子靶向药物Sorafenib是否作用于该通路而降低肝癌复发转移。本研究体外实验构建了肝癌细胞缺氧模型，证实缺氧状态下肝癌细胞HIF-1α/VEGFA通路表达增加，并导致肝癌细胞迁移及侵袭能力增强，而Sorafenib不仅可诱导肝癌细胞凋亡并可抑制HIF-1α/VEGFA通路表达；通过体内实验验证肝癌不完全消融后HIF-1α/VEGFA表达增加，MVD增多，是肝癌射频消融后残余瘤快速进展及转移的可能原因，而Sorafenib可抑制HIF-1α/VEGFA通路表达，并进一步抑制肝癌的快速进展及转移。本研究通过探讨Sorafenib对HIF-1α/VEGFA通路的作用，为其应用于肝癌RFA术后患者防止复发转移提供理论上的依据。