重组人血管内皮抑制素联合TACE对兔VX-2肝癌模型微血管密度及Notch通路的影响  

Influences of recombinant human endostatin combined with TACE on microvessel density and Notch pathway of rabbit model of VX-2 liver cancer

作　　者：杨波 李玉伟 潘峰 刘玉宇 YANG Bo;LI Yuwei;PAN Feng;LIU Yuyu(Department of Interventional Medicine,Affiliated Hospital of Southwest Medical University,Sichuan Luzhou 646000,China.)

机构地区：[1]西南医科大学附属医院介入医学部,四川泸州646000

出　　处：《现代肿瘤医学》2023年第8期1428-1434,共7页Journal of Modern Oncology

基　　金：西南医科大学校级基金资助计划项目(编号:2017-ZRQN-141)。

摘　　要：目的:探讨重组人血管内皮抑制素(rhES)联合经导管动脉内化疗栓塞术(TACE)对果蝇双翅边缘缺刻同源基因(Notch)通路的调控作用,及对兔VX-2肝癌模型微血管密度(MVD)的影响。方法:取新西兰大白兔60只,随机取50只用肿瘤种植法建立兔VX-2肝癌模型,分为模型组、TACE组、TACE+rhES组(TACE术+rhES溶液0.75 mg/kg)、Notch激活剂jagged1组(TACE术+jagged1溶液13 ng/kg)、TACE+rhES+jagged1组(TACE术+rhES溶液0.75 mg/kg+jagged1溶液13 ng/kg),每组10只,未造模的10只兔作为正常对照组。治疗2周后,行CT成像,获取兔肿瘤周边血流量(BF)、血容量(BV)、毛细血管表面渗透面积(PS)值;称取兔体重并处死取肝脏,计算肝脏指数、肿瘤体积;免疫组化法检测肝脏MVD;蛋白免疫印迹法(Western blot)检测癌灶周边非坏死肝脏组织Notch、Notch配体(jagged1)、血管内皮生长因子(VEGF)、活化蛋白1(AP-1)蛋白相对表达水平。结果:与正常对照组相比,模型组兔出现饮食、活动减少及精神萎靡现象,肿瘤结节为暗红色且出现坏死、液化及囊性改变等病理损伤,肝脏指数、肿瘤体积、肝组织MVD、Notch、jagged1、VEGF、AP-1蛋白表达升高(P<0.05),体质量、BF、BV及PS水平下降(P<0.05)。与模型组相比,TACE组肿瘤结节为乳白色,肿瘤体积显著下降(P<0.05),其余指标差异无统计学意义(P>0.05);jagged1组兔精神萎靡及肿瘤组织坏死程度加重,肝脏指数、肿瘤体积、MVD、Notch、jagged1、VEGF、AP-1蛋白表达升高(P<0.05),体质量、BF、BV及PS水平下降(P<0.05);TACE+rhES组兔饮食、精神等好转,肿瘤组织坏死程度减轻,肝脏指数、肿瘤体积、Notch、jagged1、VEGF、AP-1蛋白表达降低(P<0.05),体质量、BF、BV及PS水平升高(P<0.05)。与TACE+rhES组相比,TACE+rhES+jagged1组上述指标变化趋势相反且有统计学差异(P<0.05)。结论:TACE+rhES联合治疗可通过抑制Notch/jagged1信号通路激活,抵抗肝癌模型兔肿瘤血管生成。Objective:To investigate the regulatory effect of recombinant human endostatin(rhES)combined with transcatheter arterial chemoembolization(TACE)on drosophila double wing margin nicked homologous gene(Notch)pathway and its influence on microvessel density(MVD)of the rabbit model of VX-2 liver cancer.Methods:Fifty of sixty New Zealand white rabbits were randomly selected to establish the VX-2 liver cancer model by tumor implantation,and they were grouped into model group,TACE group,TACE+rhES group(TACE+rhES solution in 0.75 mg/kg),Notch activator jagged1 group(TACE+jagged1 solution in 13 ng/kg),TACE+rhES+jagged1 group(TACE+rhES solution in 0.75 mg/kg+jagged1 solution in 13 ng/kg),with 10 rabbits in each group,and the 10 rabbits without model were served as normal control group.After 2 weeks of treatment,CT imaging was performed to obtain the blood flow(BF),blood volume(BV)and capillary surface permeability area(PS)around the tumor of rabbits.The weight of rabbits was weighed,the rabbits were sacrificed and their livers were taken to calculate the liver index and tumor volume.Immunohistochemistry was used to detect the MVD of liver.Western blot was used to detect the relative protein expression levels of Notch,Notch ligand(jagged1),vascular endothelial growth factor(VEGF),and activated protein 1(AP-1)in non-necrotic liver tissue around the tumor.Results:Compared with the normal control group,the rabbits in the model group had decreased diet,decreased activity and apathy,and the tumor nodules were dark red with pathological damages such as necrosis,liquefaction and cystic changes.The liver index,tumor volume,MVD,protein expressions of Notch,jagged1,VEGF and AP-1 were higher(P<0.05),and the body weight and levels of BF,BV and PS were lower(P<0.05).Compared with the model group,the tumor nodule in TACE group was milky white,and the tumor volume was obviously lower(P<0.05),and there was no obvious difference in other indicators(P>0.05).The degrees of mental depression and tumor necrosis in jagged1 group increased,and th

关 键 词：重组人血管内皮抑制素 经导管动脉内化疗栓塞术 肝癌 果蝇双翅边缘缺刻同源基因(Notch)通路 微血管密度 

分 类 号：R735.7[医药卫生—肿瘤]