环氧化酶－2基因启动子甲基化及表达与胃黏膜病变的关系

Association between promoter methylation of cyclooxygenase-2 and expression, and precancerous gastric lesions in a high-risk population

目的探讨环氧化酶-2（COX-2）基因启动子区甲基化水平和蛋白表达与胃黏膜病变的关系，并对其相关的影响因素进行研究。方法以1201例患有不同胃黏膜病变的高危人群为研究对象，采用免疫组织化学方法检测COX-2表达，用亚硫酸氢钠．变性高效液相色谱（DHPLC）对COX-2启动子甲基化率进行定量分析，采用^13C尿素呼气实验（^13C—UBT）对幽门螺旋杆菌（Hpylori）感染状况进行测定。结果COX-2甲基化率中位数随胃黏膜病变的加重逐渐升高，在浅表性胃炎和慢性萎缩性胃炎（SG／CAG）、肠上皮化生（IM）及不确定性异型增生和异型增生（Ind DYS／DYS）病变中分别为10．6％、11．8％、13．8％，各病变组之间差异有统计学意义（χ^2=8．312，P=0．016）。分层分析显示，在Hpy／or／感染阴性病例中，COX-2甲基化率仍随病变加重明显升高，在SG／CAG、IM、Ind DYS／DYS病变中其中位数分别为8．8％、10．6％、14．1％（χ^2=6．629，P=0．036）。进一步分析发现，COX-2甲基化率随着COX-2表达强度的增强而降低，由COX-2弱阳性表达的13．3％降至强阳性表达的7．6％（χ^2=10．400，P=0．015）。结论COX-2启动子甲基化水平与胃黏膜病变程度及Hpylori感染状况密切相关，并与COX-2表达强度呈负相关，说明COX-2启动子区异常甲基化可能在胃黏膜病变的演变过程中起重要作用。

Objective To evaluate the relationship between cyclooxygenase-2 （COX-2） methylation and expression, and precancerous gastric lesions. Methods Methylation status of COX-2 was evaluated by quantitative denaturing high performance liquid chromatngraghy （DHPLC） in 1201 subjects with different gastric lesions. COX-2 expression was assessed by immunohistochemistry and Helicobacter pylori （H pylori ） infection status was determined by ^13C-urea breath test （^13 C-UBT）. Results The percent of COX-2 methylation was increased steadily with the severity of gastric lesions, showing 10. 6% of which with superficial gastritis/chronic atrophic gastritis （SG/CAG）, 11.8% with intestinal metaptasia （IM） and 13.8% with indefinite dysplasia/dysplasia （ Ind DYS/DYS） （ χ^2 = 8. 312, P = 0. 016）. Stratified analysis indicated that the percents of COX-2 methylation in subjects with H py/or/ negative still increased with the severity of gastric lesions,of 8. 8% in SG/CAG,10. 6% in IM and 14. 1% in Ind DYS/DYS （χ^2 = 6. 629, P =0. 036）. Moreover, the methylated proportion of COX-2 was negatively associated with the expression in gastric lesions, from 13.3% with mild expression to 7.6% with strong expression （ χ^2 = 10. 400, P = O. 015）. Conclusion Our findings indicated that COX-2 methylation was significantly associated with precancerous gastric lesions and H pylori infection, suggesting that promoter methylation of COX-2 might play an important role in the progression of gastric lesions.