缺氧诱导因子-1α在胃癌中的表达及其与化疗疗效关系的研究

Relationship between the expression of hypoxia-inducible factor-1α and chemotherapy response in gastric carcinoma

目的观察缺氧诱导因子（HIF）-1α在胃癌组织中的表达及其与化疗疗效和临床预后的关系。方法对52例未接受过任何放化疗的中晚期胃癌患者予以四氢叶酸（CF）、氟尿嘧啶（5-FU）、草酸铂（L-OHP）为基础的联合化疗方案（CF200mg／m^2静脉滴注2h。5-FU1500mg／m^2静脉持续滴注46h，L-OHP85mg／m^2静脉滴注2h），分别于第1天和第14天给药．4周为1个周期．至少需完成4个周期的化疗。化疗结束后进行疗效评价。并对患者加以随访以作生存分析。同时对该52例患者的胃癌组织标本进行免疫组织化学染色，检测HIF-1α、P糖蛋白（P—gP）和多药耐药相关蛋白（MRP4）在胃癌组织中的表达，另取27例正常胃黏膜作对照。结果HIF—1α、P—gP和MRP4在胃癌组织中的阳性表达率分别为53．9％、51．9％和57．7％，在正常胃黏膜组织中分别为0、18．5％和14．8％。两组间的差异均有统计学意义（均P〈0．05）。HIF-1α阳性表达者化疗有效率14．3％，显著低于HIF—1α阴性表达者（50．0％，P〈0．05）。HIF-1α阳性表达组中位无进展生存期（PFS）为4．9个月，中位总生存期（OS）为8．8个月，1年和2年生存率分别为37．5％和21．5％；而HIF-1α阴性表达组中位PFS为8．4个月．中位OS为12．6个月．1年和2年生存率分别为51．2％和33．5％：两组生存期的差异具有统计学意义（P〈0．05）。结论HIF-1α表达可作为临床上预测胃癌化疗疗效及临床预后的的指标之一。

Objective To evaluate the relationship of hypoxia-inducible factor （HIF）-1α expression with chemotherapy response in gastric cancer and its clinical outcome. Methods Leucovofin （CF） and 5-fluorouracil （5-FU） in combination with oxaliplatin （L-OHP） were used in 52 patients with gastric carcinoma （GC） at advanced stage. CF 200 mg/m^2 was intravenous drop for 2 h at day 1 and day 14. 5-FU 1500 mg/m^2 was continuously intravenous drop for 46 h at day 1 and day 14. L-OHP 85 mg/m^2 was intravenous drop for 2 h at day 1 and day 14. Four-week was one cycle. All the patients received 4 cycles of chemotherapy at least. Chemotherapy response and clinical outcome were evaluated. Immunohistochemistry was used to examine the protein expressions of HIF-1α,P-gp and MRP4 by tissue microarray in GC. Twenty-seven normal gastric tissue samples were used as control group. Results The positive expression rates of HIF-1α,P-gp and MRP4 in tumor samples were 53.9%, 51.9% and 57.7% respectively, which were significantly higher than those in normal gastric tissues （0, 18.5% and 14.8% respectively）（P〈0.05）. In cases with positive expression of HIF-1α, the response rate was 14.3%; whereas in cases with negative expression of HIF-1α, the response rate was 50.0%. There was significant difference between two groups （P〈0.05）. In patients of HIF-1α positive expression,the median progression-free survival time was 4.7 months,the median survival time was 8.8 months,and 1-year, 2-year survival rates were 37.5% and 21.5% respectively. In patients of HIF-1α negative expression, the median progression-free survival time was 8.4 months,the median survival time was 12.6 months,and 1-year, 2-year survival rates were 51.2% and 33.5% respectively. There were significant differences between two groups （P〈0.05）. Conclusion HIF-1α expression may be a useful indicator to predict the chemotherapy response and clinical outcome in gastrie carcinoma.