【作者】 王冠；

【导师】 张春清；

【作者基本信息】 山东大学 ， 内科学（专业学位）， 2013， 硕士

【摘要】 目的：研究原发性肝癌患者TACE(Transhepatic artery chemoembolization,经导管肝动脉栓塞化疗)前后血清中VEGF(Vascular endothelial growth factor,血管内皮生长因子)、CTGF(Connective tissue growth factor,结缔组织生长因子)、HIF-1α (Hypoxia inducible factor-1α,乏氧诱导因子-1α)和OPN(Osteopontin,骨桥蛋白)的动态变化,探讨肝癌患者血清中这四种因子浓度的高低与临床及影像学特征的关系以及四因子之间的相关性,从而分析TACE对肝癌转移和侵袭潜能的影响。方法：选择2012年6月至2013年2月在山东省立医院东院消化内科住院治疗的31例原发性肝细胞肝癌(Hepatocellular carcinoma, HCC)患者为研究对象,分别于患者TACE术前、术后1天、术后3天、术后5天及术后7天留取血清标本。15例健康对照者留取一次血清标本。用ELISA (enzyme-linked immunosorbentassay,酶联免疫吸附法)检测血清标本中VEGF、CTGF、HIF-1α和OPN的浓度及TACE前后的动态变化；分析VEGF、CTGF、HIF-1α和OPN术前浓度及TACE前后的波动幅度与患者肿瘤直径、远处转移、门脉癌栓、HBsAg等临床及影像学特征间的联系；统计学分析采用SPSS17.0统计软件进行t检验和Spearman相关分析,认为P<0.05具有显著性差异。结果：(1)肝癌患者TACE术前血清中VEGF, CTGF, HIF-1α和0PN水平均明显高于对照组(均为P<0.05)；VEGF和CTGF术后1天、3天、5天均高于术前(均为P<0.05),其中VEGF高峰期出现于术后1天,CTGF高峰期出现于术后3天,术后7天均与术前无明显差异(均为P>0.05)；HIF-1α和OPN术后1天、3天、5天、7天均高于术前(均为P<0.05),且高峰期均出现于术后1天；VEGF、CTGF、HIF-1α和OPN术后7天均较术后1天明显降低(均为P<0.05)。(2) VEGF、CTGF、HIF-1α和OPN术前浓度及TACE前后的波动幅度均与术前存在远处转移呈显著相关(均为P<0.05),VEGF术前浓度与肿瘤直径大于5cm呈显著相关(P<0.05),CTGF和OPN的波动幅度与存在门脉癌栓、HBsAg阳性呈显著相关(均为P<0.05)。(3)肝癌患者血清中HIF-1α与VEGF的水平呈正相关(r=0.870,P<0.001),HIF-1α与OPN的水平呈正相关(r=0.807,P<0.001),OPN与VEGF的水平呈正相关(r=0.712,P<0.001)。结论：(1)VEGF、CTGF、HIF-1α和OPN术后1天、3天、5天均高于术前,VEGF、HIF-1Q和OPN高峰期出现于术后1天,CTGF高峰期出现于术后3天,提示与TACE所形成的乏氧微环境有关。VEGF、CTGF、HIF-1α和OPN术后7天均较术后1天明显降低,其中VEGF和CTGF术后7天的浓度与术前无明显差异。(2)VEGF、CTGF、HIF-1α和OPN术前浓度均与存在远处转移显著相关,VEGF术前浓度与肿瘤直径大于5cm显著相关,提示四因子均与肿瘤的生长及侵袭、转移能力有关。TACE前后VEGF、CTGF、HIF-1α和OPN的波动幅度均与存在远处转移显著相关,CTGF和OPN的波动幅度还与存在门脉癌栓、HBsAg阳性呈显著相关。(3)肝癌患者血清中HIF-1α与VEGF、OPN的水平分别呈正相关,提示HIF-1α可能通过上调VEGF和OPN的水平促进肿瘤的血管形成,增加肿瘤的侵袭性。VEGF与OPN的水平呈正相关,说明OPN可能通过上调VEGF的水平以促进肿瘤血管生成。更多还原

【Abstract】 Objective:The study was focused on the dynamic changes of serum VEGF (Vascular endothelial growth factor)、CTGF(Connective tissue growth factor)、HIF-1α (Hypoxia inducible factor-1α)and OPN (Osteopontin)before and after TACE(Transhepatic artery chemoembolization) in primary hepatocellular carcinoma (HCC)patients, to explore the relationship between clinic and imaging features and the four factors. Then,we can analysis the effect of TACE on invasion and metastasis of HCC.Methods:We chose31patients with HCC treated in Shandong Provincial Hospital from June2012to February2013. Serum samples were collected from each patient before TACE,1day,3days,5days and7days after TACE.15cases of healthy persons as a healthy control group. The dynamic changes of serum VEGF、CTGF、HIF-1α and OPN were measured by ELISA. Then analysis the link between VEGF, CTGF, HIF-1α and OPN preoperative levels and fluctuation ranges with clinic and imaging features,such as tumor diameter, distant metastasis, portal vein invasion and HBsAg. T test and spearman correlational analyzation were carried out on the basis of SPSS17.0.Results:(1) Serum levels of VEGF, CTGF, HIF-1a and OPN in HCC patients before TACE were significantly higher than that in the control group (P<0.05); The concentration of VEGF and CTGF in1day,3days and5days after TACE were higher than preoperative (P<0.05), and VEGF concentration peak appeared at1day after TACE, while CTGF appeared at3days after TACE, both showed no significant differences between7days after TACE and the preoperative (P>0.05); The concentration of HIF-1a and OPN after1day,3days,5days,7days were higher than the preoperative (P<0.05), and both concentration peak appeared at1day after TACE; The concentration of VEGF, CTGF, HIF-1a and OPN after7days were significantly lower than lday after TACE(P<0.05).(2) VEGF, CTGF, HIF-1α and OPN preoperative levels and fluctuation ranges were significantly correlated with the presence of distant metastasis before TACE(P<0.05), VEGF preoperative level was significantly correlated with greater tumor diameter (P<0.05), the fluctuation ranges of CTGF and OPN were significantly correlated with portal vein invasion and positive HBsAg (P<0.05).(3) In the serum of HCC patients, HIF-1a and VEGF levels were positively correlated (r=0.870, P<0.001), HIF-1α and OPN levels were positively correlated (r=0.807, P<0.001), OPN and VEGF levels were positively correlated (r=0.712, P<0.001).Conclusion:(1) Serum levels of VEGF, CTGF, HIF-1a and OPN in HCC patients before TACE were significantly higher than that in the control group, suggesting that they played a role in the occurrence and development of liver cancer. VEGF, CTGF, HIF-1α and OPN in lday,3days,5days after TACE were higher than the preoperative, and VEGF, HIF-1α and OPN peak period appeared one day after TACE,while CTGF appeared3days after TACE, which related to hypoxic microenvironment caused by TACE. The concentration of VEGF, CTGF, HIF-1α and OPN after7days were significantly lower than lday after TACE, especially VEGF and CTGF after7days showed no significant difference with the preoperative.(2) VEGF, CTGF, HIF-1a and OPN preoperative levels were significantly correlated with distant metastasis, VEGF preoperative level was significantly correlated with greater tumor diameter, suggesting that the four factors were associated with the growth and invasion of tumor. The fluctuation ranges of the four factors were significantly correlated with distant metastasis, besides, the fluctuation ranges of CTGF and OPN were also significantly correlated with portal vein invasion and positive HBsAg.(3) In the serum of HCC patients, HIF-1a and VEGF, OPN were respectively positively correlated, suggesting that HIF-1α may promote tumor angiogenesis by upregulating VEGF and OPN level. VEGF and OPN levels were positively correlated, suggesting that OPN may promote tumor angiogenesis by upregulating VEGF level.更多还原