IL-18BPc在原发性肝癌中的表达及IL-18BPc在肝癌血管生成中作用的初步研究
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摘要
目的检测C型白细胞介素18结合蛋白(Interleukin-18 binding protein c, IL-18BPc)、血管内皮生长因子(Vascular endothelial growth factor,VEGF)及人定向造血干细胞抗原(Human hematopoietic progenitor cell antigen,CD34)三种蛋白在人原发性肝癌(PHC)组织中的表达及其相关性,初步探讨IL-18BPc在人原发性肝癌血管生成中的意义。并检测原发性肝癌患者循环血液中IL-18BP浓度,探讨血清IL-18BP水平在原发性肝癌病程中的意义。
方法通过动物免疫制备兔抗人IL-18BPc多克隆抗体,利用免疫组织化学技术(SP法)检测34例原发性肝癌组织中IL-18BPc、VEGF及CD34蛋白的表达,并与34例相对应的癌旁肝组织及5例正常肝组织比较。同时比较原发性肝癌组织中IL-18BPc、VEGF阳性表达者的微血管密度(MVD)计数与相应的阴性表达者的MVD计数之间的差异。酶联免疫吸附测定(ELISA)检测46例原发性肝癌及41例肝硬化患者外周静脉血IL-18BP浓度;分析肝癌血清IL-18BP浓度与性别、年龄、分期、肝硬化、腹水、AFP水平、HBsAg及血清总胆红素之间的关系。
结果成功制备兔抗人Pro-IL-18BPc多克隆抗体,其效价为1:30000～1:80000。34例原发性肝癌组织IL-18BPc、VEGF的阳性表达率分别为85.29%、76.47%, MVD计数50.29±11.14 /200倍视野;34例癌旁肝组织IL-18BPc、VEGF的阳性表达率分别为38.24%和32.35%,MVD计数为13.81±5.99/200倍视野;正常肝组织几乎无IL-18BPc、CD34表达,VEGF阳性表达率为25.00%。IL-18BPc在肝癌癌巢中、癌周缘、癌旁肝组织及正常肝脏组织中表达的免疫组织化学评分值分别为4.04±1.60、2.78±1.19、1.58±1.26及0.53±0.52,组间差异有统计学意义(P<0.01)。IL-18BPc和VEGF在原发性肝癌组织中的表达呈正相关(r=0.357,P<0.05)。肝癌组织中IL-18BPc阳性表达者的MVD计数为52.43±10.38/200倍视野,其阴性表达者的MVD计数为37.94±6.70/200倍视野,两者比较有统计学差异(P<0.01);肝癌组织中VEGF阳性表达者的MVD计数为53.09±10.39/200倍视野,其阴性表达者的MVD计数为41.22±8.72/200倍视野,两者比较有统计学差异(P<0.01)。肝癌组血清IL-18BP浓度为12.36±9.96 ng/ml,肝硬化组血清IL-18BP浓度为7.69±3.22 ng/ml,两者比较有显著统计学差异;肝癌组血清IL-18BP水平与肿瘤分期、合并肝硬化及腹水有关,与性别、年龄、AFP水平、HBsAg以及血清总胆红素无关。
结论IL-18BPc在原发性肝癌组织中为阳性表达,其在原发性肝癌发生和发展过程中起着重要作用,并与原发性肝癌新生血管生成可能有关。原发性肝癌患者血清IL-18BP水平可能反映其肿瘤大小、分期及肝功能状态。
Objective: To explore the significance of interleukin-18 binding protein c (IL-18BPc) in angiogenesis of human primary hepatic carcinoma (PHC) through detection of the expression of IL-18BPc, vascular endothelial growth factor (VEGF) and human hematopoietic progenitor cell antigen (CD34) protein in human PHC tissue sections.
Methods: New Zealand rabbits were immunized by Pro-IL-18BP-C and Freund’s adjuvant. IL-18BPc, VEGF and CD34 three proteins in 34 paraffin embedded samples of PHC, compared with that in 34 liver tissues out of corresponding tumor margin as well as 5 cases of normal liver tissues. Microvessel density (MVD) of IL-18BPc, VEGF protein positive expression tissues were compared with that of IL-18BPc, VEGF protein negative expression tissues, respectively, in PHC. Measured IL-18BP plasma levels in 46 patients with PHC and 41 patients with liver cirrhosis by ELISA, analysed the relations of IL-18BP plasma levels with sex, age, clinical stage, liver cirrhosis, ascites, AFP, HBsAg and serum total bilirubin in patients with PHC.
Results: The titer of Pro-IL-18BPc polyclonal antibody was 1:30000 to 1:80000.The percentage of IL-18BPc, VEGF protein positive expression was 85.29% and 76.47%, respectively. and MVD count was 50.29±11.14 /200VF, in PHC. IL-18BPc, VEGF and CD34 staining reactions were significantly higher in PHC tissue than surrounding-tumor tissue, liver tissue out of tumor margin and normal liver tissue. There was positive correlation between the expressions of IL-18BPc and VEGF in PHC (r=0.357,P<0.05).In PHC, MVD of IL-18BPc protein positive expression tissues was significantly higher than that of IL-18BPc protein negative expression tissues and MVD of VEGF protein positive expression tissues was also significantly higher than that of VEGF protein negative expression tissues. IL-18BP plasma levels were significantly higher in patients with PHC than in patients with liver cirrhosis. In patients with PHC, IL-18BP plasma levels correlated with malignant tumor stage, complicated with cirrhotics and complicated with ascites.
Conclusion: IL-18BPc may play a role in human primary hepatic carcinoma and malignant progress, and this role may correlate with angiogenesis of PHC. IL-18BP plasma levels may reflect malignant tumor volume,stage and liver function in PHC patients.
方法通过动物免疫制备兔抗人IL-18BPc多克隆抗体,利用免疫组织化学技术(SP法)检测34例原发性肝癌组织中IL-18BPc、VEGF及CD34蛋白的表达,并与34例相对应的癌旁肝组织及5例正常肝组织比较。同时比较原发性肝癌组织中IL-18BPc、VEGF阳性表达者的微血管密度(MVD)计数与相应的阴性表达者的MVD计数之间的差异。酶联免疫吸附测定(ELISA)检测46例原发性肝癌及41例肝硬化患者外周静脉血IL-18BP浓度;分析肝癌血清IL-18BP浓度与性别、年龄、分期、肝硬化、腹水、AFP水平、HBsAg及血清总胆红素之间的关系。
结果成功制备兔抗人Pro-IL-18BPc多克隆抗体,其效价为1:30000～1:80000。34例原发性肝癌组织IL-18BPc、VEGF的阳性表达率分别为85.29%、76.47%, MVD计数50.29±11.14 /200倍视野;34例癌旁肝组织IL-18BPc、VEGF的阳性表达率分别为38.24%和32.35%,MVD计数为13.81±5.99/200倍视野;正常肝组织几乎无IL-18BPc、CD34表达,VEGF阳性表达率为25.00%。IL-18BPc在肝癌癌巢中、癌周缘、癌旁肝组织及正常肝脏组织中表达的免疫组织化学评分值分别为4.04±1.60、2.78±1.19、1.58±1.26及0.53±0.52,组间差异有统计学意义(P<0.01)。IL-18BPc和VEGF在原发性肝癌组织中的表达呈正相关(r=0.357,P<0.05)。肝癌组织中IL-18BPc阳性表达者的MVD计数为52.43±10.38/200倍视野,其阴性表达者的MVD计数为37.94±6.70/200倍视野,两者比较有统计学差异(P<0.01);肝癌组织中VEGF阳性表达者的MVD计数为53.09±10.39/200倍视野,其阴性表达者的MVD计数为41.22±8.72/200倍视野,两者比较有统计学差异(P<0.01)。肝癌组血清IL-18BP浓度为12.36±9.96 ng/ml,肝硬化组血清IL-18BP浓度为7.69±3.22 ng/ml,两者比较有显著统计学差异;肝癌组血清IL-18BP水平与肿瘤分期、合并肝硬化及腹水有关,与性别、年龄、AFP水平、HBsAg以及血清总胆红素无关。
结论IL-18BPc在原发性肝癌组织中为阳性表达,其在原发性肝癌发生和发展过程中起着重要作用,并与原发性肝癌新生血管生成可能有关。原发性肝癌患者血清IL-18BP水平可能反映其肿瘤大小、分期及肝功能状态。
Objective: To explore the significance of interleukin-18 binding protein c (IL-18BPc) in angiogenesis of human primary hepatic carcinoma (PHC) through detection of the expression of IL-18BPc, vascular endothelial growth factor (VEGF) and human hematopoietic progenitor cell antigen (CD34) protein in human PHC tissue sections.
Methods: New Zealand rabbits were immunized by Pro-IL-18BP-C and Freund’s adjuvant. IL-18BPc, VEGF and CD34 three proteins in 34 paraffin embedded samples of PHC, compared with that in 34 liver tissues out of corresponding tumor margin as well as 5 cases of normal liver tissues. Microvessel density (MVD) of IL-18BPc, VEGF protein positive expression tissues were compared with that of IL-18BPc, VEGF protein negative expression tissues, respectively, in PHC. Measured IL-18BP plasma levels in 46 patients with PHC and 41 patients with liver cirrhosis by ELISA, analysed the relations of IL-18BP plasma levels with sex, age, clinical stage, liver cirrhosis, ascites, AFP, HBsAg and serum total bilirubin in patients with PHC.
Results: The titer of Pro-IL-18BPc polyclonal antibody was 1:30000 to 1:80000.The percentage of IL-18BPc, VEGF protein positive expression was 85.29% and 76.47%, respectively. and MVD count was 50.29±11.14 /200VF, in PHC. IL-18BPc, VEGF and CD34 staining reactions were significantly higher in PHC tissue than surrounding-tumor tissue, liver tissue out of tumor margin and normal liver tissue. There was positive correlation between the expressions of IL-18BPc and VEGF in PHC (r=0.357,P<0.05).In PHC, MVD of IL-18BPc protein positive expression tissues was significantly higher than that of IL-18BPc protein negative expression tissues and MVD of VEGF protein positive expression tissues was also significantly higher than that of VEGF protein negative expression tissues. IL-18BP plasma levels were significantly higher in patients with PHC than in patients with liver cirrhosis. In patients with PHC, IL-18BP plasma levels correlated with malignant tumor stage, complicated with cirrhotics and complicated with ascites.
Conclusion: IL-18BPc may play a role in human primary hepatic carcinoma and malignant progress, and this role may correlate with angiogenesis of PHC. IL-18BP plasma levels may reflect malignant tumor volume,stage and liver function in PHC patients.
引文
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