巨噬细胞移动抑制因子在肝癌诊断中的价值

Value of macrophage migration inhibitory factor in the diagnosis of hepatocellular carcinoma

目的探讨巨噬细胞移动抑制因子（MIF）在肝癌诊断中的价值。方法试验分为测试研究和验证研究。回顾性分析2004年1月至5月复旦大学附属中山医院收治的269例肝癌患者（测试肝癌组）和390例对照人群（测试对照组）；8月至12月收治的173例肝癌患者（验证肝癌组）和257例对照人群（验证对照组）；2005年1月收治的80例行根治性肝切除的肝癌患者的临床资料。收集测试研究和验证研究受试者术前体格检查的血浆标本和行根治性肝切除的肝癌患者术前、术后3、7、30d的血浆标本，同时收集测试肝癌组患者术后的肝癌组织和癌旁（距肿瘤1cm）组织标本。采用ELISA法检测血浆中MIF水平，免疫组织化学法检测组织中MIF表达情况。非正态分布数据用中位数（四分位数间距）[M（QR）]表示，组间比较采用Mann—WhitneyU检验，血浆和组织中MIF的关系采用Spearman相关分析，ROC曲线分析MIF的诊断价值。结果在测试研究中，测试肝癌组和测试对照组受试者血浆MIF中位值分别为85．7μg/L（58．8μg／L）和15．5μg／L（31．6μg／L）。其中测试对照组中的肝硬化患者、良性肝病患者和健康体检者血浆MIF中位值分别为24．9μg／L（12．6μg／L）、12．5μg／L（7．3Ixg／L）、13．2Ixg／L（7．7μg／L），两组各受试者血浆MIF比较，差异有统计学意义（F=54．235，P〈0．05）。ROC曲线结果表明，当血浆MIF为35．3μg／L时，可获得最大的曲线下面积。验证肝癌组与验证对照组比较，AUC值、灵敏度、特异度分别为92．1％、90．7％．93．4％。肝癌患者术前和术后3、7、30d血浆MIF中位值分别为81．0μg／L（54．0μg／L）、76．1斗g／L（47．5μg／L）、50．9μg／L（40．7μg／L）、18．7μg／L（15．1μg／L），呈时间依赖性降低，术后30d基本恢复到正常范围内。肝癌组织和癌旁组织MIF的中位表达强度分别为0．083和0．007，两者比较，差异有统计学意义（U=3．975，P〈0．05）。肝癌患者血浆中MIF和相应的肝癌组织内MIF表达呈正相关（r；0．759，P〈0．05）。结论MIF与肝癌发生、发展密切相关，MIF可作为肝癌诊断的潜在分子标志物。

Objective To investigate the diagnostic value of macrophage migration inhibitory factor （MIF） for hepatocellular carcinoma （HCC）. Methods The research was divided into 2 parts, including testing research and confirmatory research. The clinical data of 269 patients with HCC （ group A） and 390 individuals （including 135 patients with hepatic cirrhosis, 106 with benign hepatic diseases and 149 healthy individuals, control group A） who were admitted to the Zhongshan Hospital of Fudan University from January to May, 2004, and 173 patients with hepatic cancer （group B） and 257 individuals （including 86 patients with hepatic cirrhosis, 79 with benign hepatic diseases and 92 healthy individuals, control group B） who were admitted from August to December, 2004, and 80 patients with HCC who received radical hepatic resection in January 2005 were retrospectively analyzed. Samples of plasma of patients in the group A and individuals in the control group A were collected before operation. Samples of plasma of patients received radical hepatic resection were collected preoper- atively and at postoperative day 3, 7 and 30. HCC and adjacent issues of patients in the group A were collected. The levels of MIF in the plasma and tissues were detected by enzyme-linked immunosorbent assay （ELISA） and immunohistochemistry, respectively. Non-normal distribution data were described as M（QR）. Differences between the groups were analyzed by using the Mann-Whitney U test, and the relationship between the levels of MIF in the plasma and tissues was detected by the Spearman correlation coefficient. The diagnostic value of MIF was analyzed by the ROC curve. Results The levels of MIF in the plasma of patients in the group A and individuals in the control group A were 85.7 ~xg/L （58.8 ~g/L） and 15.5 I^g/L（31.6 I^g/L）, respectively. The levels of MIF in the plasma of the patients with hepatic cirrhosis, benign hepatic diseases and healthy individuals were 24.9 txg/L （ 12.6 txg/L）, 12.5 I^g/L（7.3 ~g/L） and 13.2 ~g/L （7.7 I^g/L）, respectively. There was a significant differ- ence in the level of MIF between the group A and the control group A （ F = 54. 235, P 〈 0.05 ）. The area under the ROC curve reached peak when the level of MIF in the plasma was 35.3 i.~g/L. Compared with the control group B, the values of AUC, sensitivity and specificity were 92.1% , 90.7% and 93.4% in the group B. The levels of MIF of the patients with HCC before operation and at 3, 7, and 30 days after operation were 81.0 μg/L（54.0μg/L）, 76.1 g/L（47.5 μg/L）, 50.9 μg/L （40.7 μg/L） and 18.7 μg,/L （15.1 μg/L）, respectively. The levels of MIF decreased with time passed by, and were back to normal at 30 days after the operation. The median expressions of MIF in the HCC and adjacent issues were 0. 083 and 0. 007, respectively, with a significant difference （U = 3. 975, P 〈 0.05 ）. The expression of MIF in the plasma was positively correlated with its expression in the HCC tissue （ r = 0. 759, P 〈 0. 05 ）. Conclusion MIF plays an important role in the genesis and development of HCC and has potential to be one of the molecular markers for the diagnosis of HCC.