抑制残癌细胞上皮间质转化能降低肝动脉结扎增强的肝癌转移潜能  

Inhibition of epithelial-mesenchymal transition represses metastastic potential of hepatocellular carcinoma enhanced by hepatic arterial occlusion in mice

作　　者：刘亮 徐华祥 王文权[2] 汤钊猷[2] 

机构地区：[1]复旦大学附属肿瘤医院胰腺肝胆外科复旦大学上海医学院肿瘤学系,上海200032 [2]复旦大学肝癌研究所复旦大学附属中山医院肝外科

出　　处：《中华普通外科杂志》2012年第2期123-126,共4页Chinese Journal of General Surgery

基　　金：基金项目：国家自然科学基金资助项目（81172005）;上海市自然科学基金资助项目（11ZRl407000）;复旦大学附属肿瘤医院院级基金资助项目（YJ201002）

摘　　要：目的探讨抑制残癌细胞上皮-间质转化对肝动脉断流后肝癌增强的转移潜能的影响。方法采用MHCC97肝癌细胞系和52只BALB／c—nu／nu裸鼠，建立转移性人肝癌裸鼠原位移植并肝动脉结扎（hepaticarteryligation，HAL）模型。另12只荷瘤裸鼠行假手术设为对照。分别观察肝动脉结扎＋阻滞剂LY294002以及肝动脉结扎＋不同剂量干扰素ot（intererin-ot，IFN—α）对移植瘤生长和肺转移率的影响。体外将肝癌细胞MHCC97置于缺氧环境中培养。Westernblot检测细胞和移植瘤内HIF—1α、E．cadherin、N—cadherin、Twist表达。结果肝动脉结扎虽然减小肝癌移植瘤体积（2002．97±331．28）mm^3VS．（3921．23±786．21）mm^3，t=4．052，P〈0．01），但增加荷瘤裸鼠肺转移率（10／12VS．4／12，P〈0．05）。联合阻滞剂LY294002治疗不能进一步抑制肝癌生长，但显著减少裸鼠肺转移（I／6vs．10／12VS．100％，P〈0．05）。中等以上剂量的IFN-α（7．5×10^6U／kg）显著降低肝动脉结扎诱导的肺转移率（0／6VS．2／6VS．100％，P〈0．01，P〈0．05）。对移植瘤和细胞样本的分析证实阻滞剂LY294002或中等以上剂量的IFN．仪均抑制缺氧肝癌细胞内N．cadherin和Twist上调，增加E—cadherin表达。结论阻断肝癌细胞上皮-间质转化能够抑制缺氧诱导的肝癌侵袭、转移。ObjectiveS＇To investigate the effects of^inhibiting epithelial mesenchymal transition （EMT） on metastastic potential of hepatocellular carcinoma （HCC） enhanced by hepatic arterial occlusion in mice. Methods Using a metastatic human HCC orthotopic nude mice model （ MHCC97）, the effects of hepatic artery ligation （HAL） alone, combination of HAL and phosphatidylinositol 3-kinase （PI3K） inhibitor LY29g002, or combination of HAL and interferon-α （IFN-α） on the growth of planted human HCC cells and pulmonary metastasis were evaluated, respectively. The cells and tumor tissues specimens were analyzed through expression of Akt, p-Akt, E-cadhein, N-cadherin and Twist. Results HAL inhibits tumor growth （2002. 97 ± 331.28 ） mm^3 vs. （ 3921.23 ± 786.21 ） mm^3, t = 4. 052, P 〈 0.01 ）, while promoting pulmonary metastatsis （10/12 vs. 4/12, P 〈 0. 05 ）. HAL combined with LY294002 represses significantly enhanced pulmonary metastasis rate by HAL alone （0/6 vs. 6/6, P 〈 0.01 ）. Moderate-dose IFN-α （7. 5 × 10^6 U/kg） combined with HAL failed to further reduce tumor volume compared with that of HAL alone, but inhibited markedly pulmonary metastasis （2/6 vs. 6/6, P 〈 0.05 ）. The augmented level of N-cadherin and Twist in tumor tissues due to HAL reduced by LY294002 or 7. 5 × 10^6 U/kg IFN-α. The arrest of EMT by LY294002 or IFN-α in HAL-treated xenografts was further demonstrated by the in vitro response of hypoxic cells to both agents. Condusions Inhibition of EMT in HCC cells could repress enhanced metastastic potential due to heoatic arterial occlusion.

关 键 词：癌 肝细胞 肿瘤转移 缺氧 肝动脉阻断 上皮-间质转化 

分 类 号：R735.7[医药卫生—肿瘤]