缺氧诱导因子-α和血管内皮素-1及血管内皮生长因子在胃肠道间质瘤中的表达及意义

Expression and significance of hypoxia inducible factor-la and endothelin-I and vascular endothelialgrowth factor in gastrointestinal stromal tumor

目的探讨缺氧诱导因子-1α（HIF-1α）、血管内皮素-1（ET-1）和血管内皮生长因子（VEGF）在胃肠道间质瘤（GIST）中的表达关系及其对患者预后判断的价值。方法收集2003年1月至2006年12月中南大学湘雅医院（50例）、湖南省邵阳市中医院（36例）行手术治疗的86例GIST患者肿瘤标本，采用免疫组织化学染色方法检测标本中HIF-1α、ET-1和VEGF的表达。计数资料采用r检验，应用Spearman等级相关分析处理HIF-1α、ET-1和VEGF之间的相关性。Kaplan—Meier法计算患者生存率，生存分析比较采用Log—rank检验。结果86例患者中，HIF-1仅阴性23例、阳性30例、强阳性33例，阳性表达率为73．3％（63／86）；ET-1阴性29例、阳性28例、强阳性29例，阳性表达率为66．3％（57／86）；VEGF阴性24例、阳性26例、强阳性36例，阳性表达率为72．1％（62／86）。HIF-1α、ET-1和VEGF的表达两两均呈正相关（r=0．594，0．655，0．347，P〈0．05）；上述3种检测指标与GIST的美国国立卫生研究院（NIH）危险度分级、浸润转移、肿瘤直径和核分裂象有关（，=15．565、10．841、12．574、21．125，8．171、10．002、10．354、17．317，14．710、16．230、11．116、18．886，P〈0．05）；而与患者的性别、年龄、肿瘤原发部位无关（X2=0．059、0．071、5．070，0．468、0．074、1．665，0．231、0．370、3．712，P〉0．05）；进-步分析发现：上述3种检测指标阳性表达率随GISTNIH危险度分级的升高、出现浸润转移和肿瘤直径的增大而增加。86例患者随访率为91．9％（79／86），3、5年生存率分别为82％和69％。中位随访时间为40．2个月（2—66个月）。HIF-1仪、ET．1和VEGF阳性患者的5年生存率分别为42％、45％和42％，显著低于阴性患者的64％、65％和63％（，=6．325，6．124，6．287，P〈0．05）。结论HIF-1d、ET-1和VEGF在GIST中的表达两两呈正相关，这3种检测指标提示肿瘤的恶性程度及患者预后。

Objective To investigate the expression and significance of hypoxia inducible factor-1α （ HIF-1α）, endothelin-1 （ET-1） and vascular endothelial growth factor （VEGF） in gastrointestinal stromal tumor （GIST）. Methods Eighty-six samples of GIST specimens were collected from Xiangya Hospital （50 cases） and Shaoyang Chinese Medicine Hospital （36 cases） from January 2003 to December 2006. The expressions of HIF-1α, ET- 1 and VEGF in the GIST were detected by immunohistochemieal staininng. The relationship between HIF-1α, ET-1 and VEGF was analyzed by using the Spearman rank correlation. The survival rates were calculated by using the Kaplan-Meier method, and the survival was analyzed using the Log-rank test. The count data were analyzed using the chi-square test. Results The expression of HIF-1 ct was negative in 23 cases, positive in 30 cases, strongly positive in 33 cases, and the overall positive rate was 73.3% （63/86） ; the expression of ET-1 was negative in 29 cases, positive in 28 cases and strongly positive in 29 cases, and the overall positive rate was 66.3% （57/86） ;the expression of VEGF was negative in 24 cases, positive in 26 cases, strongly positive in 36 cases, and the overall positive rate was 72.1% （62/86）. There was a positive corelation between the expressions of HIF-1α, ET-1 and VEGF （r =0. 594, 0.655, 0. 347, P 〈 0.05）. The positive expressions of HIF-1α, ET-1 and VEGF were correlated with National Institute of Health （NIH） risk stratification, infiltration and metastasis, tumor diameter and number of nuclear division of GIST （X2= 15. 565, 10. 841, 12. 574, 21. 125; 8. 171, 10. 002, 10. 354, 17. 317; 14. 710, 16. 230, 11. 116, 18. 886, P〈0.05）, but not with the gender, age and the initial occurring position of the tumor （X2= 0. 059, 0. 071, 5. 070 ; 0. 468, 0. 074, 1. 665 ; O. 231,0. 370, 3. 712, P 〉 0.05）. The positive expression rates of HIF-1α, ET-1 and VEGF increased as the increase of the malignant level of GIST, tumor infiltration and metastasis and the tumor diameter. The follow up rate was 91.9% （79/86）, and the 3- and 5-year survival rates were 82% and 69%, respectively. The median survival rate was 40.2 months （range, 2-66 months）. The 5-year survival rates of patients with positive expressions of HIF-1α, ET-1 and VEGF were 42%, 45% and 42%, respectively, and the 5-year survival rates of patients with negative expressions of HIF-1α, ET-1 and VEGF were 64% , 65% and 63%, respectively. The 5-year survival rates of patients with positive expressions of HIF-1α, ET-1 and VEGF were significantly lower than those with negative expressions of HIF-1α, ET-1 and VEGF （X2 = 6. 325, 6. 124, 6. 287, P 〈 0.05）. Conclusion There is a positive correlation between the expressions of HIF-1α, ET- 1 and VEGF. HIF- 1 oL, ET- 1 and VEGF could be served as important predictors for the prognosis of patients with GIST.