【摘要】 目的研究增殖-凋亡失衡在结直肠癌发生过程中的作用,并探讨其动态变化的分子机制。方法以二甲基肼诱发昆明小鼠结直肠癌。分别于给药后第1 2,1 8,2 4周处死动物,观察各时点模型组及对照组小鼠结直肠黏膜的病理变化。多阶段动态观察增殖细胞和凋亡细胞的分布和程度;并分别应用RT-PCR,免疫组化和W estern blot检测小鼠结直肠黏膜组织中p 2 1waf1,GADD 4 5和Bax的表达。结果诱癌过程中,模型组小鼠结直肠黏膜上皮依次出现轻、中、重度不典型增生、腺瘤和腺癌。模型组结直肠非癌黏膜各时点的PCNA表达明显高于对照组(P<0.0 1);从正常黏膜→不典型增生→腺瘤→癌,PCNA表达逐渐增高,至癌阶段PCNA表达明显增强,各组间比较差异均有显著性(P<0.0 1)。模型组结直肠在从正常黏膜至癌的演变过程中,增殖与凋亡的比值逐渐增高,差异有显著性(P<0.0 1);模型组结直肠黏膜在从正常黏膜至腺瘤的过程中,p 2 1waf1,GADD 4 5和BaxmRNA表达和蛋白表达均逐渐增强;而癌组织中,3种基因的表达水平明显减弱。结论在二甲基肼诱发的昆明小鼠结直肠癌的发生过程中,结直肠黏膜存在着增殖与凋亡的失衡;p 2 1waf1,GADD 4 5和Bax 3种抑癌基因与结直肠癌的发生有关。更多还原

【Abstract】 Objective To study the effect of imbalance of proliferation and apoptosis in the development of colorectal carcinoma(CRC),and the molecular mechanism of the dynamic change.Methods ORC was(induced) with dimethylhydrazine(DMH) in male mice of Kimming strain.The mice were killed in batches in the 12th,18th and 24th weeks of carcinoma induction.The distribution and extent of proliferation and(apoptosis) of the colorectal mucosa,at various intervals,were dynamically observed.Three genes,p21waf1,Bax and Gadd45 were analyzed by RT-PCR,immunohistochemistry and Western blot.Results During the course of carcinoma induction,the mucosas of the model mice showed sequential changes of atypital(hyperplasia),adenoma,and carcinoma.Compared with control group,the PCNA expression of the model group mice was significantly higher(P<0.01);and the expression was also progressively increased from normal mucosaatypital hyperplasiaadenomacarcinoma(P<0.01).The highest PCNA expression was observed in cancer.Meanwhile,the ratio of proliferation to apoptosis also progressively increased(P<0.01).The three genes,p21waf1,GADD45 and Bax were increased during the mucosa development from normal mucosa to(adenoma),whereas their expression was very weak in cancer.Conclusions During the mice colon carcinogenesis(induced) by DMH,the colorectal mucosa appears to be in a disequilibrium of proliferation and apoptosis;colon(carcinogenesis) is related to the 3 suppressor genes,p21waf1,GADD45 and Bax.更多还原