广西原发性肝癌抗血管生成治疗机制及围手术期肝功能评估研究

The study on the mechanism of antiangiogenesis and liver function evaluation of primary hepatocellular carcinoma in Guangxi

目的探讨广西原发性肝癌抗血管生成治疗机制和评估围手术期肝功能。方法通过体外分子生物学实验、体内动物实验、耐药实验结合肝癌患者生存资料进行分析;通过观察104例肝癌患者声脉冲辐射力成像(acoustic radiation force impulse,ARFI)评分与术后标准残肝体积(SRLV)进行直线回归分析;检测术前尿8-羟基脱氧鸟苷(8-OHd G)及外周血T淋巴细胞亚群CD4+、CD8+表达。结果 COX-2/PGE2信号通路可调控肝癌中血管内皮生长因子(VEGF)的上游靶点蛋白缺氧诱导因子2α(HIF-2α)的活性;PEG-SS-PLL有效地转染si VEGF,其细胞毒性可忽略不计,且在体外和体内均显著降低了VEGF在mRNA和蛋白水平的表达,抑制了肿瘤生长;重度代偿不全的SRLV的临界值为503 ml/m2。术前ARFI评分及术后SRLV进行直线回归方程为SRLV(ml/m2)=149.6×ARFI评分(m/s)+194.1。术前尿8-OHd G水平显著高于对照组[(16.15±4.96)ng/mg Cr vs(12.13±4.66)ng/mg Cr]。结论 COX-2/PGE2通路的特异性抑制剂Meloxicam或Celecoxib可明显增强肝癌分子靶向药物索拉菲尼的药物敏感性,PEG-SS-PLL/si VEGF可能被应用于肝细胞癌的抗血管生成基因治疗;联合SRLV及肝纤维化程度测定对原发性肝癌术前安全切肝量评估有重要指导价值,对伴中、重度肝纤维化病例安全SRLV临界值为503 ml/m2;尿8-OHd G在肝癌诊治及疗效评价中有较高应用价值。

Objective To explore the mechanism of antiangiogenesis and the evaluation of perioperative liver function in primary hepatocellular carcinoma in Guangxi. Methods The survival data of liver cancer patients were analyzed by molecular biology experiment,animal experiment and drug resistance experiment. A linear regression analysis was performed to observe the acoustic radiation force impulse（ ARFI） score and postoperative standard residual liver volume（ SRLV） in 104 patients with liver cancer. Preoperative urinary 8-hydroxydeoxyguanosine（ 8-OHd G）and peripheral blood T lymphocyte subgroup CD4＋and CD8＋expressions were detected. Results COX-2/PGE2 signaling pathways regulated VEGF activity via regulating HIF-2 α activity; PEG-SS-PLL effectively transfected the si VEGF,and its cytotoxicity was negligible,and the expressions of VEGF in mRNA and the protein levels significantly decreased both in vitro and in vivo,inhibiting tumor growth. The critical value of SRLV with severe compensation was503 ml/m2. The linear regression equation of preoperative ARFI score and postoperative SRLV was： SRLV（ ml/m2） =149. 6 × ARFI score（ m/s） ＋ 194. 1. Preoperative urinary 8-OHd G level was significantly higher than that of the control group [（ 16. 15 ± 4. 96） ng/mg Cr vs（ 12. 13 ± 4. 66） ng/mg Cr]. Conclusion The specific inhibitors of COX-2/PGE2 pathway,meloxicam or celecoxib can significantly enhance the drug sensitivity of liver cancer molecular targeted drug sorafenib. PEG-SS-PLL/si VEGF may be applied to the anti-angiogenesis gene therapy of hepatocellular carcinoma. Combining SRLV with the detection of hepatic fibrosis degress has important guiding value for the primary hepatocellular carcinoma patients receiving preoperative assessment of the amount of liver resection. For the cases of medium or severe liver fibrosis,the safety of SRLV threshold is 503 ml/m～2. Urinary 8-OHd G has high application value in the diagnosis and treatment of liver cancer.