遗传性非息肉病性结直肠癌中环氧合酶2表达及其与错配修复基因表达和微卫星不稳定的相关性

Expression of cyclooxygenase-2 and relationship with mismatch repaire gene and microsatellite instability in hereditary non-polyposis colorectal cancer

目的探讨遗传性非息肉病性结直肠癌（HNPCC）腺瘤及癌组织中环氧合酶2（COX-2）的表达及其与错配修复（MMR）基因蛋白表达、微卫星不稳定（MSI）之间的关系。方法来源于33个HNPCC家系的大肠腺瘤28例、大肠癌14例，随机留取经病理确诊的32例散发大肠腺瘤和24例散发大肠癌标本作为对照；采用免疫组织化学和PCR技术，检测腺瘤及癌组织中cox-2、MMR基因（hMLH1、hMSH2、hMSH6）蛋白表达及BAT-25、BAT-26、D2S123、D5S346、D17S2505个微卫星位点的MSI状态。结果COX-2在HNPCC大肠腺瘤及HNPCC大肠癌组织中高表达率分别为53．6％（15／28）、42．9％（6／14），在散发大肠腺瘤和散发大肠癌中高表达率分别为62．5％（20／32）、91．7％（22／24），HNPCC大肠癌中的COX-2表达明显低于散发大肠癌（P〈0．05）。HNPCC大肠癌中MMR蛋白表达缺失率、高度微卫星不稳定（MSI-H）发生率[均为71．4％（10／14）]均明显高于散发大肠癌[均为12．5％（3／24），均P〈0．05]。10例MMR蛋白表达缺失的HNPCC大肠癌中，8例为COX-2低表达；4例MMR蛋白表达阳性的HNPCC大肠癌全部为COX-2高表达。在MMR表达缺失的HNPCC大肠癌、HNPCC大肠腺瘤、散发大肠癌中COX-2的表达均显著少于MMR表达阳性者（均P〈0．05）。MSI—H的HNPCC大肠癌、HNPCC大肠腺瘤、散发大肠癌中COX-2低表达率分别为80．0％（8／10）、66．7％（12／18）、66．7％（2／3）；与微卫星稳定（MSS）组比较差异均有统计学意义（均P〈0．05）。结论与散发性大肠癌相比，COX-2在HNPCC大肠癌组织中表达明显减少；COX-2在大肠腺瘤及癌组织中的表达率与MMR蛋自表达缺失和MSI-H呈明显的负相关；COX-2、MMR蛋白表达、MSI的检测对于进一步研究大肠肿瘤的发病途径及干预治疗具有重要意义。

Objective To investigate the expression of cyclooxygenase （COX）-2 and the relationship between COX-2, mismatch repaire gene （MMR） proteins and microsatellite instability （MSI） in HNPCC. Methods Twenty-eight cases of adenomas and 14 cases of carcinomas were collected from 33 HNPCC families patients by colonoscopy. Sporadic adenomas （ n = 32） and carcinomas （ n = 24） were used as a control group. The expressions of COX-2 and mismatch repair gene hMLH1, hMSH2, hMSH6 proteins were examined by immunohistochemistry. MSI were analyzed by using PCR with BAT25, BAT26, D2S123, D5S346 and D17S250 loci. Results The COX-2 high-expression rates were 53.6% （15/28） and 42. 9% （6/ 14）in HNPCC adenomas and carcinomas, and were 62. 5% （20/32） and 91.7% （22/24） in sporadic adenomas and carcinomas. COX-2 expression was lower in HNPCC carcinomas than that of sporadic carcinomas （P 〈 0. 05）. MMR deficiency rate and positive rate of MSI-H were both 71.4% （10/14） respectively in HNPCC carcinomas. It was higher than that in sporadic colorectal carcinomas [ both 12. 5% （3/24） 3. Eight （80. 0% ） COX-2 low-expression were observed in 10 HNPCC carcinomas with MMR- deficient system while 4 COX-2 high-expression cases were observed in 4 HNPCC carcinomas with MMR- proficient system. COX-2 expression was lower in HNPCC carcinomas and adenomas, sporadic carcinomas with MMR-deficient system than that of MMR-proficient （ P 〈 0. 05 ）. The COX-2 low-expression rates were 80.0% （8/10）, 66.7% （12/18） and 66.7% （2/3） in HNPCC adenomas, HNPCC carcinomas and sporadic carcinomas with MSI-H. Cox-2 expression was lower in HNPCC and sporadic carcinomas （adenocarcinomas） with MSI-H than that of MSS （P 〈 0. 05 ）. Conclusion Compared with sporadic carcinomas, the COX-2 expression was lower in HNPCC carcinomas. There was negative correlation between COX-2 expression and MMR-deficient （MSI-H）. The detection of COX-2, MMR protein and MSI is of important significance in further studying the pathogenesis and interventional therapy of colorectal neoplasms.